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Programmed death-ligand 1 (PD-L1) is a promising target for cancer immunotherapy due to its ability to inhibit T cell activation; however, its expression on various noncancer cells may cause on-target off-tumor toxicity when designing PD-L1-targeting Chimeric Antigen Receptor (CAR) T cell therapies. Combining rational design and directed evolution of the human fibronectin-derived monobody scaffold, PDbody was engineered to bind to PD-L1 with a preference for a slightly lower pH, which is typical in the tumor microenvironment. PDbody was further utilized as a CAR to target the PD-L1-expressing triple negative MDA-MB-231 breast cancer cell line. To mitigate on-target off-tumor toxicity associated with targeting PD-L1, a Cluster of Differentiation 19 (CD19)-recognizing SynNotch IF THEN gate was integrated into the system. This CD19-SynNotch PDbody-CAR system was then expressed in primary human T cells to target CD19-expressing MDA-MB-231 cancer cells. These CD19-SynNotch PDbody-CAR T cells demonstrated both specificity and efficacy in vitro, accurately eradicating cancer targets in cytotoxicity assays. Moreover, in an in vivo bilateral murine tumor model, they exhibited the capability to effectively restrain tumor growth. Overall, CD19-SynNotch PDbody-CAR T cells represent a distinct development over previously published designs due to their increased efficacy, proliferative capability, and mitigation of off-tumor toxicity for solid tumor treatment.

Aim: Characterize the logistical challenges faced by healthcare professionals (HCPs), patients and caregivers during the chimeric antigen receptor T-cell (CAR T) treatment process for non-Hodgkin lymphoma patients. Materials & methods: HCPs in the US and UK experienced with CAR T administration participated in interviews and completed a web-based survey. Results: A total of 133 (80 US, 53 UK) HCPs participated. Two or more logistical challenges were identified by ≥60% of respondents across all stages of the CAR T process. Commonly reported challenges were lengthy waiting periods, administrative and payer-related barriers, limited healthcare capacity, caregiver support and (particularly in the US) patient out-of-pocket costs. Conclusion: The CAR T treatment process presents numerous challenges, highlighting an unmet need for more convenient therapies. Plain Language Summary Chimeric antigen receptor T-cell (CAR T) therapy is a new treatment for patients with non-Hodgkin lymphoma that have not responded to other types of treatment. CAR T therapy uses a person's own immune cells (T cells), which are modified in a laboratory to attack cancer cells. While CAR T therapy has the potential to be effective, there are challenges associated with the treatment process. In this study, we surveyed 133 healthcare professionals (HCPs) in the United States and United Kingdom to understand their experiences with logistical challenges involved in navigating the CAR T process. More than 60% of participants identified two or more logistical challenges at every stage of the CAR T treatment process. The most commonly reported challenges included long waiting periods, limited room at hospitals, availability of caregivers to support patients and issues related to out-of-pocket costs, travel and lodging for patients who are treated at specialized centers. In the United States, challenges related to insurance coverage and out-of-pocket costs for patients were highlighted. More than half of HCPs reported that patients' cancer getting worse while waiting to receive CAR T was a reason why patients may not proceed to treatment. While operational improvements might address some challenges in the CAR T treatment process, these findings highlight the need for more convenient, readily available and easily administered therapies for patients with non-Hodgkin lymphoma. Article highlights While chimeric antigen receptor T-cell (CAR T) therapy represents an advancement in the treatment of non-Hodgkin lymphoma, it is associated with a number of logistical challenges for patients, caregivers and healthcare professionals (HCPs). We surveyed physicians, nurses and other HCPs involved in the various stages of CAR T therapy administration in the US and UK to characterize logistical challenges at each stage of the CAR T process. Initial in-depth qualitative interviews (n = 25) of HCPs highlighted lack of caregiver support, time and administration, travel and accommodations and payer access as key themes. In a subsequent quantitative survey of HCPs (n = 133), more than 60% of respondents identified at least two logistical challenges faced at every stage of CAR T administration. Respondents most commonly reported challenges related to lengthy waiting periods, slow approval processes, limited capacity and availability of caregiver support. More than half of respondents reported rapid disease progression as a common reason why eligible patients do not proceed to CAR T infusion. The availability of caregiver support was selected as a logistical challenge present at every stage of the CAR T treatment process. Respondents highlighted out-of-pocket costs, travel and lodging challenges throughout the CAR T process, although out-of-pocket costs and insurance-related challenges were more pronounced in the US than in the UK. This study adds to the growing body of literature addressing the logistical challenges associated with CAR T therapy. Infographic [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR) T-cell therapy has attracted considerable attention since its recent endorsement by the Food and Drug Administration, as it has emerged as a promising immunotherapeutic modality within the landscape of oncology. This study explores the prognostic utility of [18F] Fluorodeoxyglucose positron emission tomography ([18F]FDG PET) in lymphoma patients undergoing CAR T-cell therapy. Through meta-analysis, pooled hazard ratio (HR) values were calculated for specific PET metrics in this context. Methods: PubMed, Scopus, and Ovid databases were explored to search for relevant topics. Dataset retrieval from inception until March 12, 2024, was carried out. The primary endpoints were impact of specific PET metrics on overall survival (OS) and progression-free survival (PFS) before and after treatment. Data from the studies were extracted for a meta-analysis using Stata 17.0. Results: Out of 27 studies identified for systematic review, 15 met the criteria for meta-analysis. Baseline OS analysis showed that total metabolic tumor volume (TMTV) had the highest HR of 2.66 (95% CI: 1.52-4.66), followed by Total-body total lesion glycolysis (TTLG) at 2.45 (95% CI: 0.98-6.08), and maximum standardized uptake values (SUVmax) at 1.30 (95% CI: 0.77-2.19). TMTV and TTLG were statistically significant (p < 0.0001), whereas SUVmax was not (p = 0.33). For PFS, TMTV again showed the highest HR at 2.65 (95% CI: 1.63-4.30), with TTLG at 2.35 (95% CI: 1.40-3.93), and SUVmax at 1.48 (95% CI: 1.08-2.04), all statistically significant (p ≤ 0.01). The DSUVmax was a significant predictor for PFS with an HR of 2.05 (95% CI: 1.13-3.69, p = 0.015). Conclusion: [18F]FDG PET parameters are valuable prognostic tools for predicting outcome of lymphoma patients undergoing CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This review article explores the potential of CAR T cell therapy in treating cholangiocarcinoma (CCA), a highly aggressive and difficult-to-treat cancer of the bile ducts. With conventional therapies offering limited success, this article highlights the innovative approach of using immune cell therapy, particularly CAR T cells, to improve outcomes for CCA patients. The review discusses the tumor microenvironment's role in disease progression and the challenges of implementing CAR T cell therapy in solid tumors. By summarizing current research, clinical trials, and the evolving landscape of precision medicine, this article aims to provide a comprehensive understanding of the future prospects for immunotherapy in CCA, emphasizing the need for continued advancements in this promising field. Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, with poor prognosis and limited treatment options. Traditional therapies, such as surgery, chemotherapy, and radiation, have shown limited efficacy, especially in advanced cases. Recent advancements in immunotherapy, particularly T cell-based therapies like chimeric antigen receptor T (CAR T) cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR)-based therapies, have opened new avenues for improving outcomes in CCA. This review provides a comprehensive overview of the current state of T cell therapies for CCA, focusing on CAR T cell therapy. It highlights key challenges, including the complex tumor microenvironment and immune evasion mechanisms, and the progress made in preclinical and clinical trials. The review also discusses ongoing clinical trials targeting specific CCA antigens, such as MUC1, EGFR, and CD133, and the evolving role of precision immunotherapy in enhancing treatment outcomes. Despite significant progress, further research is needed to optimize these therapies for solid tumors like CCA. By summarizing the most recent clinical results and future directions, this review underscores the promising potential of T cell therapies in revolutionizing CCA treatment. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor T-cell (CAR-T) therapy, a rapidly emerging treatment for cancer that has gained momentum since its approval by the FDA in 2017, involves the genetic engineering of patients' T cells to target tumors. Although significant therapeutic benefits have been observed, lifethreatening adverse pulmonary events have been reported. Methods: Using SAS 9.4 with MedDRA 26.1, we retrospectively analyzed data from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database, covering the period from 2017 to 2023. The analysis included the Reporting Odds Ratio Proportional Reporting Ratio Information Component and Empirical Bayes Geometric Mean to assess the association between CAR-T cell therapy and adverse pulmonary events (PAEs). Results: The FAERS database recorded 9,400 adverse events (AEs) pertaining to CAR-T therapies, of which 940 (10%) were PAEs. Among these CAR-T cell-related AEs, hypoxia was the most frequently reported (344 cases), followed by respiratory failure (127 cases). Notably, different CAR-T cell treatments demonstrated varying degrees of association with PAEs. Specifically, Tisa-cel was associated with severe events including respiratory failure and hypoxia, whereas Axi-cel was strongly correlated with both hypoxia and tachypnea. Additionally, other CAR-T therapies, namely, Brexu-cel, Liso-cel, Ide-cel, and Cilta-cel, have also been linked to distinct PAEs. Notably, the majority of these PAEs occurred within the first 30 days post-treatment. The fatality rates varied among the different CAR-T therapies, with Tisa-cel exhibiting the highest fatality rate (43.6%), followed by Ide-cel (18.8%). Conclusion: This study comprehensively analyzed the PAEs reported in the FAERS database among recipients of CAR-T cell therapy, revealing conditions such as hypoxia, respiratory failure, pleural effusion, and atelectasis. These CAR-T cell therapy-associated events are clinically significant and merit the attention of clinicians and researchers. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy is a promising treatment for pediatric patients with relapsed or refractory B cell acute lymphoblastic leukemia (R/R B ALL). Cytokine release syndrome (CRS) is a common toxicity after CAR T cell therapy and fever is often the first symptom. Differentiating CRS from infection after CAR T cell therapy can be challenging. Plasma microbial cell free DNA (mcfDNA) is a novel diagnostic tool which allows for qualitative and quantitative assessment of over 1000 organisms. This pilot study sought to characterize mcfDNA results in pediatric patients with R/R B ALL in the first 2 months after CAR T cell therapy. [ABSTRACT FROM AUTHOR]

Light chain (AL) amyloidosis is a plasma cell disorder distinguished from multiple myeloma (MM) by the degree of organ involvement due to tissue deposition of misfolded proteins. Treatments for AL amyloidosis have largely been borrowed from those developed for patients with MM. High-dose chemotherapy followed by autologous stem cell transplant (ASCT) has historically been associated with the best outcomes. The recent incorporation of daratumumab into up front therapy represents a significant advance and has changed the treatment paradigm, calling into question the role of ASCT. The development of very active novel immune and cellular therapies, specifically B cell maturation antigen (BCMA)-directed therapies, has similarly been transformative for patients with MM and is now being studied in patients with AL amyloidosis. These include chimeric antigen receptor (CAR) T cells, bispecific antibodies, and antibody drug conjugates. Although limited, preliminary data in patients with relapsed and refractory AL amyloidosis are showing promising results, and it is expected that the treatment landscape for AL amyloidosis will continue to evolve. Particular attention to safety, potential for organ recovery, and quality of life will be important when evaluating new treatments and/or treatment paradigms. [ABSTRACT FROM AUTHOR]

This article discusses recent research on CD4 CAR T cells and their role in CAR T cell therapy (CTT). CD4 CAR T cells have traditionally been seen as providing support to CD8 CAR T cells, but recent studies have shown that CD4 CAR T cells can directly kill tumor cells and control their growth. However, CD4 CAR T cells have also been found to contribute to cytokine release syndrome (CRS), a serious adverse event in CTT. The article highlights the need for a deeper understanding of the roles and mechanisms of CD4 CAR T cells in order to design safer and more effective CAR T cell products. Additionally, the article discusses the impact of CD4 T cells on CAR T cell manufacturing, suggesting that co-culturing CD4 T cells with CD8 T cells can improve the quantity and quality of CAR T cells. The article concludes by emphasizing the importance of leveraging the benefits of CD4 T cells while minimizing their negative effects in CTT. [Extracted from the article]

Standard-of-care treatment for Glioblastoma Multiforme (GBM) is comprised of surgery and adjuvant chemoradiation. Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated disease-modifying activity in GBM and holds great promise. Radiation, a standard-of-care treatment for GBM, has well-known immunomodulatory properties and may overcome the immunosuppressive tumor microenvironment (TME); however, radiation dose optimization and integration with CAR T cell therapy is not well defined. Murine immunocompetent models of GBM were treated with titrated doses of stereotactic radiosurgery (SRS) of 5, 10, and 20 Gray (Gy), and the TME was analyzed using Nanostring. A conditioning dose of 10 Gy was determined based on tumor growth kinetics and gene expression changes in the TME. We demonstrate that a conditioning dose of 10 Gy activates innate and adaptive immune cells in the TME. Mice treated with 10 Gy in combination with mCAR T cells demonstrated enhanced antitumor activity and superior memory responses to rechallenge with IL13Rα2-positive tumors. Furthermore, 10 Gy plus mCAR T cells also protected against IL13Rα2-negative tumors through a mechanism that was, in part, c-GAS-STING pathway-dependent. Together, these findings support combination conditioning with low-dose 10 Gy radiation in combination with mCAR T cells as a therapeutic strategy for GBM. [ABSTRACT FROM AUTHOR]

Adoptive cell transfer with chimeric antigen receptor (CAR)-expressing T cells can induce remarkable complete responses in cancer patients. Therapeutic success has been correlated with central and stem cell-like memory T cell subsets in the infusion product, which are better able to drive efficient CAR T cell in vivo expansion and long-term persistence. We previously reported that inhibition of the mitochondrial pyruvate carrier (MPC) during mouse CAR T cell culture induces a memory phenotype and enhances antitumor efficacy against melanoma. Here, we use a novel MPC inhibitor, MITO-66, which robustly induces a stem cell-like memory phenotype in CD19-CAR T cells generated from healthy donors and patients with relapsed/refractory B cell malignancies. MITO-66-conditioned CAR T cells were superior in controlling human pre-B cell acute lymphoblastic leukemia in mice. Following adoptive cell transfer, MITO-66-conditioned CAR T cells maintained a memory phenotype and protected cured mice against tumor rechallenge. Furthermore, in an in vivo B cell leukemia stress model, CD19-CAR T cells generated in the presence of MITO-66 largely outperformed clinical-stage AKT and PI-3Kδ inhibitors. Thus, we provide compelling preclinical evidence that MPC inhibition with MITO-66 during CAR T cell manufacturing dramatically enhances their antitumor efficacy, thereby paving the way to clinical translation.

Fahreddin Palaz,1,2 Mehmet Ozsoz,3 Ali Zarrinpar,4,5 Ilyas Sahin5,6 1Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 2Faculty of Medicine, Hacettepe University, Ankara, Turkey; 3Department of Biomedical Engineering, Near East University, Nicosia, Turkey; 4Department of Surgery, College of Medicine, University of Florida, Gainesville, FL, USA; 5University of Florida Health Cancer Center, Gainesville, FL, USA; 6Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, FL, USACorrespondence: Ilyas Sahin, Email i.sahin@ufl.eduAbstract: Despite recent therapeutic advancements, outcomes for advanced hepatocellular carcinoma (HCC) remain unsatisfactory, highlighting the need for novel treatments. The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) gene-editing technology offers innovative treatment approaches, involving genetic manipulation of either cancer cells or adoptive T cells to combat HCC. This review comprehensively assesses the applications of CRISPR systems in HCC treatment, focusing on in vivo targeting of cancer cells and the development of chimeric antigen receptor (CAR) T cells and T cell receptor (TCR)-engineered T cells. We explore potential synergies between CRISPR-based cancer therapeutics and existing treatment options, discussing ongoing clinical trials and the role of CRISPR technology in improving HCC treatment outcomes with advanced safety measures. In summary, this review provides insights into the promising prospects and current challenges of using CRISPR technology in HCC treatment, with the ultimate goal of improving patient outcomes and revolutionizing the landscape of HCC therapeutics.Keywords: CRISPR, hepatocellular carcinoma, HCC, targeted cancer therapy, adoptive T cell immunotherapy, CAR T cell therapy

High-dose melphalan (HDM) plus autologous stem cell transplant (ASCT) remains a standard-of-care treatment approach for eligible patients with newly diagnosed multiple myeloma (NDMM) based on demonstrated superiority in terms of progression-free survival (PFS) versus nontransplant approaches. Very high rates of minimal residual disease (MRD)-negative responses are also being seen with novel triplet and quadruplet induction regimens plus HDM-ASCT. However, recent clinical trials have shown no overall survival benefit with transplant versus nontransplant approaches. Furthermore, HDM is associated with several important downsides, including acute and long-term toxicities, transient decreases in quality of life, the need for hospitalization, an increased mutational burden at relapse, and an elevated risk of second primary malignancies. In this context, given the highly heterogeneous nature of MM in the NDMM patient population, as well as the continued emergence of novel agents and treatment approaches, there is an increasing rationale for considering deferred HDM-ASCT approaches in selected patients. Approaches under investigation include MRD-adapted therapy and the use of novel immune-based therapies as alternatives to HDM-ASCT. Ongoing developments in understanding the pathobiology and prognostic factors in NDMM, plus immune profiling and routine MRD evaluation, will result in novel, HDM-sparing treatment paradigms, enabling further improvement in patient outcomes.

Abstract The application of chimeric antigen receptor (CAR) T cells in the management of hematological malignancies has emerged as a noteworthy therapeutic breakthrough. Nevertheless, the utilization and effectiveness of CAR-T cell therapy in solid tumors are still limited primarily because of the absence of tumor-specific target antigen, the existence of immunosuppressive tumor microenvironment, restricted T cell invasion and proliferation, and the occurrence of severe toxicity. This review explored the history of CAR-T and its latest advancements in the management of solid tumors. According to recent studies, optimizing the design of CAR-T cells, implementing logic-gated CAR-T cells and refining the delivery methods of therapeutic agents can all enhance the efficacy of CAR-T cell therapy. Furthermore, combination therapy shows promise as a way to improve the effectiveness of CAR-T cell therapy. At present, numerous clinical trials involving CAR-T cells for solid tumors are actively in progress. In conclusion, CAR-T cell therapy has both potential and challenges when it comes to treating solid tumors. As CAR-T cell therapy continues to evolve, further innovations will be devised to surmount the challenges associated with this treatment modality, ultimately leading to enhanced therapeutic response for patients suffered solid tumors.

Introduction: Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematological malignancies. However, its efficacy in solid tumors is limited by the immunosuppressive tumor microenvironment that compromises CAR T cell antitumor function in clinical settings. To overcome this challenge, researchers have investigated the potential of inhibiting specific immune checkpoint receptors, including A2aR (Adenosine A2 Receptor) and Tim3 (T cell immunoglobulin and mucin domain-containing protein 3), to enhance CAR T cell function. In this study, we evaluated the impact of genetic targeting of Tim3 and A2a receptors on the antitumor function of human mesothelin-specific CAR T cells (MSLN-CAR) in vitro and in vivo. Methods: Second-generation anti-mesothelin CAR T cells were produced using standard cellular and molecular techniques. A2aR-knockdown and/or Tim3-knockdown anti-mesothelin-CAR T cells were generated using shRNA-mediated gene silencing. The antitumor function of CAR T cells was evaluated by measuring cytokine production, proliferation, and cytotoxicity in vitro through coculture with cervical cancer cells (HeLa cell line). To evaluate in vivo antitumor efficacy of manufactured CAR T cells, tumor growth and mouse survival were monitored in a human cervical cancer xenograft model. Results: In vitro experiments demonstrated that knockdown of A2aR alone or in combination with Tim3 significantly improved CAR T cell proliferation, cytokine production, and cytotoxicity in presence of tumor cells in an antigen-specific manner. Furthermore, in the humanized xenograft model, both double knockdown CAR T cells and controlCAR T cells could effectively control tumor growth. However, single knockdown CAR T cells were associated with reduced survival in mice Conclusion: These findings highlight the potential of concomitant genetic targeting of Tim3 and A2a receptors to augment the efficacy of CAR T cell therapy in solid tumors. Nevertheless, caution should be exercised in light of our observation of decreased survival in mice treated with single knockdown MSLNCAR T cells, emphasizing the need for careful efficacy considerations. [ABSTRACT FROM AUTHOR]

Patients with Richter's transformation of chronic lymphocytic leukemia (CLL) to diffuse large B‐cell lymphoma (DLBCL‐RT) face a dismal prognosis. A 51‐year‐old female patient diagnosed with CLL with deletion (17p) in 2009. CLL treatment included chemoimmunotherapy and targeted substances. DLBCL‐RT was diagnosed in November 2016. After receiving an allogeneic hematopoietic stem cell transplantation, she relapsed in September 2019 and tisagenlecleucel was infused in December 2019. Cytokine release syndrome grade 2 was treated with two doses of tocilizumab and the patient was started on 140 mg ibrutinib in February 2020. Our patient remains in remission up to 4 years after CAR T‐cell treatment. [ABSTRACT FROM AUTHOR]

High-dose melphalan (HDM) plus autologous stem cell transplant (ASCT) remains a standard-of-care treatment approach for eligible patients with newly diagnosed multiple myeloma (NDMM) based on demonstrated superiority in terms of progression-free survival (PFS) versus nontransplant approaches. Very high rates of minimal residual disease (MRD)-negative responses are also being seen with novel triplet and quadruplet induction regimens plus HDM-ASCT. However, recent clinical trials have shown no overall survival benefit with transplant versus nontransplant approaches. Furthermore, HDM is associated with several important downsides, including acute and long-term toxicities, transient decreases in quality of life, the need for hospitalization, an increased mutational burden at relapse, and an elevated risk of second primary malignancies. In this context, given the highly heterogeneous nature of MM in the NDMM patient population, as well as the continued emergence of novel agents and treatment approaches, there is an increasing rationale for considering deferred HDM-ASCT approaches in selected patients. Approaches under investigation include MRD-adapted therapy and the use of novel immune-based therapies as alternatives to HDM-ASCT. Ongoing developments in understanding the pathobiology and prognostic factors in NDMM, plus immune profiling and routine MRD evaluation, will result in novel, HDM-sparing treatment paradigms, enabling further improvement in patient outcomes. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape of relapsed/refractory multiple myeloma. The current Food and Drug Administration approved CAR T cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel both target B cell maturation antigen (BCMA), which is expressed on the surface of malignant plasma cells. Despite deep initial responses in most patients, relapse after anti-BCMA CAR T cell therapy is common. Investigations of acquired resistance to anti-BCMA CAR T cell therapy are underway. Meanwhile, other viable antigenic targets are being pursued, including G protein-coupled receptor class C group 5 member D (GPRC5D), signaling lymphocytic activation molecule family member 7 (SLAMF7), and CD38, among others. CAR T cells targeting these antigens, alone or in combination with anti-BCMA approaches, appear to be highly promising as they move from preclinical studies to early phase clinical trials. This review summarizes the current data with novel CAR T cell targets beyond BCMA that have the potential to enter the treatment landscape in the near future. [ABSTRACT FROM AUTHOR]

Introduction: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor T cell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes. Methods: Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). Results: In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95% CI 2.81–38.46]) and complete response (OR 10.11 [95% CI 4.26–24.00]), and improved progression-free survival (HR 0.44 [95% CI 0.25–0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses. Conclusions: Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results. [ABSTRACT FROM AUTHOR]

The application of chimeric antigen receptor (CAR) T cells in the management of hematological malignancies has emerged as a noteworthy therapeutic breakthrough. Nevertheless, the utilization and effectiveness of CAR-T cell therapy in solid tumors are still limited primarily because of the absence of tumor-specific target antigen, the existence of immunosuppressive tumor microenvironment, restricted T cell invasion and proliferation, and the occurrence of severe toxicity. This review explored the history of CAR-T and its latest advancements in the management of solid tumors. According to recent studies, optimizing the design of CAR-T cells, implementing logic-gated CAR-T cells and refining the delivery methods of therapeutic agents can all enhance the efficacy of CAR-T cell therapy. Furthermore, combination therapy shows promise as a way to improve the effectiveness of CAR-T cell therapy. At present, numerous clinical trials involving CAR-T cells for solid tumors are actively in progress. In conclusion, CAR-T cell therapy has both potential and challenges when it comes to treating solid tumors. As CAR-T cell therapy continues to evolve, further innovations will be devised to surmount the challenges associated with this treatment modality, ultimately leading to enhanced therapeutic response for patients suffered solid tumors. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the management of relapsed and refractory myeloma, with excellent outcomes and a tolerable safety profile. High dose chemotherapy with autologous hematopoietic stem cell transplantation (AHCT) is established as a mainstream of newly diagnosed multiple myeloma (NDMM) management in patients who are young and fit enough to tolerate such intensity. This standard was developed based on randomized trials comparing AHCT to chemotherapy in the era prior to novel agents. More recently, larger studies have primarily shown a progression free survival (PFS) benefit of upfront AHCT, rather than overall survival (OS) benefit. There is debate about the significance of this lack of OS, acknowledging the potential confounders of the chronic nature of the disease, study design and competing harms and benefits of exposure to AHCT. Indeed upfront AHCT may not be as uniquely beneficial as we once thought, and is not without risk. New quadruple-agent regimens are highly active and effective in achieving a deep response as quantified by measurable residual disease (MRD). The high dose chemotherapy administered with AHCT imposes a burden of short and longterm adverse effects, which may alter the disease course and patient's ability to tolerate future therapies. Some high-risk subgroups may have a more valuable benefit from AHCT, though still ultimately suffer poor outcomes. When compared to the outcomes of CAR T cell therapy, the question of whether AHCT can or indeed should be deferred has become an important topic in the field. Deferring AHCT may be a personalized decision in patients who achieve MRD negativity, which is now well established as a key prognostic factor for PFS and OS. Reserving or re-administering AHCT at relapse is feasible in many cases and holds the promise of resetting the T cell compartment and opening up options for immune reengagement. It is likely that personalized MRD-guided decision making will shape how we sequence in the future, though more studies are required to delineate when this is safe and appropriate. [ABSTRACT FROM AUTHOR]

Autoimmune diseases with B cell–directed therapeutics approved by the US Food and Drug Administration are surprisingly diverse in clinical manifestations and pathophysiology. In this review, we focus on recent clinical and mechanistic insights into the efficacy of B cell depletion in these diverse autoimmune disorders, the rapidly expanding armamentarium of approved agents, and future approaches. The pathogenic roles for B cells include direct functions such as production of autoantibodies and proinflammatory cytokines and indirect functions via antigen presentation to T cells. The efficacy of B cell–depleting strategies varies across diseases and likely reflects the complexity of disease pathogenesis and relative contribution of B cell roles. Additionally, B cell–depleting therapies do not equally target all B cell subsets in all patients, and this likely explains some of the variability in responses. Recent reports of B cell depletion with novel chimeric antigen receptor (CAR) T cell approaches in an expanding number of autoimmune diseases highlight the potential role of B cell depletion in resetting immune tolerance. The relative importance of eliminating autoreactive B cells and plasma cells and approaches to doing so will also be discussed. [ABSTRACT FROM AUTHOR]

BackgroundChimeric antigen receptor (CAR) T-cell therapy has attracted considerable attention since its recent endorsement by the Food and Drug Administration, as it has emerged as a promising immunotherapeutic modality within the landscape of oncology. This study explores the prognostic utility of [18F]Fluorodeoxyglucose positron emission tomography ([18F]FDG PET) in lymphoma patients undergoing CAR T-cell therapy. Through meta-analysis, pooled hazard ratio (HR) values were calculated for specific PET metrics in this context.MethodsPubMed, Scopus, and Ovid databases were explored to search for relevant topics. Dataset retrieval from inception until March 12, 2024, was carried out. The primary endpoints were impact of specific PET metrics on overall survival (OS) and progression-free survival (PFS) before and after treatment. Data from the studies were extracted for a meta-analysis using Stata 17.0.ResultsOut of 27 studies identified for systematic review, 15 met the criteria for meta-analysis. Baseline OS analysis showed that total metabolic tumor volume (TMTV) had the highest HR of 2.66 (95% CI: 1.52-4.66), followed by Total-body total lesion glycolysis (TTLG) at 2.45 (95% CI: 0.98-6.08), and maximum standardized uptake values (SUVmax) at 1.30 (95% CI: 0.77-2.19). TMTV and TTLG were statistically significant (p < 0.0001), whereas SUVmax was not (p = 0.33). For PFS, TMTV again showed the highest HR at 2.65 (95% CI: 1.63-4.30), with TTLG at 2.35 (95% CI: 1.40-3.93), and SUVmax at 1.48 (95% CI: 1.08-2.04), all statistically significant (p ≤ 0.01). The ΔSUVmax was a significant predictor for PFS with an HR of 2.05 (95% CI: 1.13-3.69, p = 0.015).Conclusion[18F]FDG PET parameters are valuable prognostic tools for predicting outcome of lymphoma patients undergoing CAR T-cell therapy.

Efficient T cell engineering is central to the success of CAR T cell therapy but involves multiple time-consuming manipulations, including T cell isolation, activation, and transduction. These steps add complexity and delay CAR T cell manufacturing, which takes a mean time of 4 weeks. To streamline T cell engineering, we strategically combine two critical engineering solutions - T cell-specific lentiviral vectors and macroporous scaffolds - that enable T cell activation and transduction in a simple, single step. The T cell-specific lentiviral vectors (referred to as STAT virus) target T cells through the display of an anti-CD3 antibody and the CD80 extracellular domain on their surface and provide robust T cell activation. Biocompatible macroporous scaffolds (referred to as Drydux) mediate robust transduction by providing effective interaction between naïve T cells and viral vectors. We show that when unstimulated peripheral blood mononuclear cells (PBMCs) are seeded together with STAT lentivirus on Drydux scaffolds, T cells are activated, selectively transduced, and reprogrammed in a single step. Further, we show that the Drydux platform seeded with PBMCs and STAT lentivirus generates tumor-specific functional CAR T cells. This potent combination of engineered lentivirus and biomaterial scaffold holds promise for an effective, simple, and safe avenue for in vitro and in vivo T cell engineering. Manufacturing T cell therapies involves lengthy and labor-intensive steps, including T cell selection, activation, and transduction. These steps add complexity to current CAR T cell manufacturing protocols and limit widespread patient access to this revolutionary therapy. In this work, we demonstrate the combination of engineered virus and biomaterial platform that, together, enables selective T cell activation and transduction in a single step, eliminating multistep T cell engineering protocols and significantly simplifying the manufacturing process. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated remarkable success in treating hematological malignancies. However, its efficacy against solid tumors, including cervical cancer, remains a challenge. Hypoxia, a common feature of the tumor microenvironment, profoundly impacts CAR T cell function, emphasizing the need to explore strategies targeting hypoxia-inducible factor-1α (HIF-1α). Methods: In this study, we evaluated the effects of the HIF-1α inhibitor PX-478 on mesoCAR T cell function through in-silico and in vitro experiments. We conducted comprehensive analyses of HIF-1α expression in cervical cancer patients and examined the impact of PX-478 on T cell proliferation, cytokine production, cytotoxicity, and exhaustion markers. Results: Our in-silico analyses revealed high expression of HIF-1α in cervical cancer patients, correlating with poor prognosis. PX-478 effectively reduced HIF-1α levels in T and HeLa cells. While PX-478 exhibited dose-dependent inhibition of antigen-nonspecific T and mesoCAR T cell proliferation, it had minimal impact on antigen-specific mesoCAR T cell proliferation. Notably, PX-478 significantly impaired the cytotoxic function of mesoCAR T cells and induced terminally exhausted T cells. Discussion: Our results underscore the significant potential and physiological relevance of the HIF-1α pathway in determining the fate and function of both T and CAR T cells. However, we recognize the imperative for further molecular investigations aimed at unraveling the intricate downstream targets associated with HIF-1α and its influence on antitumor immunity, particularly within the context of hypoxic tumors. These insights serve as a foundation for the careful development of combination therapies tailored to counter immunosuppressive pathways within hypoxic environments and fine-tune CAR T cell performance in the intricate tumor microenvironment. [ABSTRACT FROM AUTHOR]

Background: Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) is a rare, mature T-cell non-Hodgkin lymphoma. The prognosis of patients with relapsed or refractory ALCL following first-line chemotherapy is extremely poor. NCCN guidelines recommend intensified chemotherapy with or without ASCT consolidation for r/r ALCL, however, this is not an effective treatment for all ALK+ALCL. Case report: Herein, we report a patient with relapsed/refractory ALK+ ALCL who received crizotinib and brentuximab vedotin as bridging therapy, followed by autologous stem cell transplantation and sequential anti-CD30 CAR T cell therapy. Conclusion: The patient achieved complete remission and long-term disease-free survival of months and continues to be followed up. The combination therapy model in this case may provide guidance for the management of relapsed/refractory ALK+ ALCL, and further prospective trials are needed to confirm its effectiveness. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) remains a global health challenge with limited treatment options and a poor prognosis for advanced-stage patients. Recent advancements in cancer immunotherapy have generated significant interest in exploring novel approaches to combat HCC. One such approach involves the unique and versatile subset of T cells known as γδ T cells. γδ T cells represent a distinct subset of T lymphocytes that differ from conventional αβ T cells in terms of antigen recognition and effector functions. They play a crucial role in immunosurveillance against various malignancies, including HCC. Recent studies have demonstrated that γδ T cells can directly recognize and target HCC cells, making them an attractive candidate for immunotherapy. In this article, we aimed to explore the role exerted by γδ T cells in the context of HCC. We investigate strategies designed to maximize the therapeutic effectiveness of these cells and examine the challenges and opportunities inherent in applying these research findings to clinical practice. The potential to bring about a revolutionary shift in HCC immunotherapy by capitalizing on the unique attributes of γδ T cells offers considerable promise for enhancing patient outcomes, warranting further investigation. [ABSTRACT FROM AUTHOR]

Immunotherapy is now established as a potent therapeutic paradigm engendering antitumor immune response against a wide range of malignancies and other diseases by modulating the immune system either through the stimulation or suppression of immune components such as CD4+ T cells, CD8+ T cells, B cells, monocytes, macrophages, dendritic cells, and natural killer cells. By targeting several immune checkpoint inhibitors or blockers (e.g., PD-1, PD-L1, PD-L2, CTLA-4, LAG3, and TIM-3) expressed on the surface of immune cells, several monoclonal antibodies and polyclonal antibodies have been developed and already translated clinically. In addition, natural killer cell-based, dendritic cell-based, and CAR T cell therapies have been also shown to be promising and effective immunotherapeutic approaches. In particular, CAR T cell therapy has benefited from advancements in CRISPR-Cas9 genome editing technology, allowing the generation of several modified CAR T cells with enhanced antitumor immunity. However, the emerging SARS-CoV-2 infection could hijack a patient's immune system by releasing pro-inflammatory interleukins and cytokines such as IL-1β, IL-2, IL-6, and IL-10, and IFN-γ and TNF-α, respectively, which can further promote neutrophil extravasation and the vasodilation of blood vessels. Despite the significant development of advanced immunotherapeutic technologies, after a certain period of treatment, cancer relapses due to the development of resistance to immunotherapy. Resistance may be primary (where tumor cells do not respond to the treatment), or secondary or acquired immune resistance (where tumor cells develop resistance gradually to ICIs therapy). In this context, this review aims to address the existing immunotherapeutic technologies against cancer and the resistance mechanisms against immunotherapeutic drugs, and explain the impact of COVID-19 on cancer treatment. In addition, we will discuss what will be the future implementation of these strategies against cancer drug resistance. Finally, we will emphasize the practical steps to lay the groundwork for enlightened policy for intervention and resource allocation to care for cancer patients. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy has emerged as a powerful therapeutic approach against a range of hematologic malignancies. While the incorporation of CD28 or 4-1BB costimulatory signaling domains into CARs revolutionized immune responses, there is an exciting prospect of further enhancing CAR functionality. Here, we investigated the design of CD19 CARs enriched with distinct Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), or Toll/IL-1 domain-containing adaptor-inducing interferon (IFN)-β (TRIF) costimulatory domains. Screening of various designs identified several candidates with no tonic activity but with increased CD19 target cell-dependent interleukin (IL)-2 production. Human T cells transduced with the selected CAR construct exhibited augmented hIL-2 and hIFN-γ induction and cytotoxicity when cocultured with CD19-positive lymphoma and solid-tumor cell lines. RNA sequencing (RNA-seq) analysis demonstrated the upregulation of some genes involved in the innate immune response and T cell activation and proliferation. In experiments on a xenogeneic solid-tumor mice model, MyD88 and TLR4 CAR T cells exhibited prolonged remission. This study demonstrates that the integration of a truncated TLR4 signaling costimulatory domain could provide immunotherapeutic potential against both hematologic malignancies and solid tumors.

Light chain (AL) amyloidosis is a plasma cell disorder distinguished from multiple myeloma (MM) by the degree of organ involvement due to tissue deposition of misfolded proteins. Treatments for AL amyloidosis have largely been borrowed from those developed for patients with MM. High-dose chemotherapy followed by autologous stem cell transplant (ASCT) has historically been associated with the best outcomes. The recent incorporation of daratumumab into up front therapy represents a significant advance and has changed the treatment paradigm, calling into question the role of ASCT. The development of very active novel immune and cellular therapies, specifically B cell maturation antigen (BCMA)-directed therapies, has similarly been transformative for patients with MM and is now being studied in patients with AL amyloidosis. These include chimeric antigen receptor (CAR) T cells, bispecific antibodies, and antibody drug conjugates. Although limited, preliminary data in patients with relapsed and refractory AL amyloidosis are showing promising results, and it is expected that the treatment landscape for AL amyloidosis will continue to evolve. Particular attention to safety, potential for organ recovery, and quality of life will be important when evaluating new treatments and/or treatment paradigms.

Despite intensive therapies, pediatric patients with relapsed or refractory solid tumors have poor outcomes and need novel treatments. Immune therapies offer an alternative to conventional treatment options but require the identification of differentially expressed antigens to direct antitumor activity to sites of disease. B7-H3 (CD276) is an immune regulatory protein that is expressed in a range of malignancies and has limited expression in normal tissues. B7-H3 is highly expressed in pediatric solid tumors including osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, Wilms tumor, neuroblastoma, and many rare tumors. In this article we review B7-H3-targeted chimeric antigen receptor (B7-H3-CAR) T cell therapies for pediatric solid tumors, reporting preclinical development strategies and outlining the landscape of active pediatric clinical trials. We identify challenges to the success of CAR T cell therapy for solid tumors including localizing to and penetrating solid tumor sites, evading the hostile tumor microenvironment, supporting T cell expansion and persistence, and avoiding intrinsic tumor resistance. We highlight strategies to overcome these challenges and enhance the effect of B7-H3-CAR T cells, including advanced CAR T cell design and incorporation of combination therapies.

IntroductionChimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematological malignancies. However, its efficacy in solid tumors is limited by the immunosuppressive tumor microenvironment that compromises CAR T cell antitumor function in clinical settings. To overcome this challenge, researchers have investigated the potential of inhibiting specific immune checkpoint receptors, including A2aR (Adenosine A2 Receptor) and Tim3 (T cell immunoglobulin and mucin domain-containing protein 3), to enhance CAR T cell function. In this study, we evaluated the impact of genetic targeting of Tim3 and A2a receptors on the antitumor function of human mesothelin-specific CAR T cells (MSLN-CAR) in vitro and in vivo.MethodsSecond-generation anti-mesothelin CAR T cells were produced using standard cellular and molecular techniques. A2aR-knockdown and/or Tim3- knockdown anti-mesothelin-CAR T cells were generated using shRNA-mediated gene silencing. The antitumor function of CAR T cells was evaluated by measuring cytokine production, proliferation, and cytotoxicity in vitro through coculture with cervical cancer cells (HeLa cell line). To evaluate in vivo antitumor efficacy of manufactured CAR T cells, tumor growth and mouse survival were monitored in a human cervical cancer xenograft model.ResultsIn vitro experiments demonstrated that knockdown of A2aR alone or in combination with Tim3 significantly improved CAR T cell proliferation, cytokine production, and cytotoxicity in presence of tumor cells in an antigen-specific manner. Furthermore, in the humanized xenograft model, both double knockdown CAR T cells and control CAR T cells could effectively control tumor growth. However, single knockdown CAR T cells were associated with reduced survival in miceConclusionThese findings highlight the potential of concomitant genetic targeting of Tim3 and A2a receptors to augment the efficacy of CAR T cell therapy in solid tumors. Nevertheless, caution should be exercised in light of our observation of decreased survival in mice treated with single knockdown MSLN-CAR T cells, emphasizing the need for careful efficacy considerations.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape of relapsed/refractory multiple myeloma. The current Food and Drug Administration approved CAR T cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel both target B cell maturation antigen (BCMA), which is expressed on the surface of malignant plasma cells. Despite deep initial responses in most patients, relapse after anti-BCMA CAR T cell therapy is common. Investigations of acquired resistance to anti-BCMA CAR T cell therapy are underway. Meanwhile, other viable antigenic targets are being pursued, including G protein-coupled receptor class C group 5 member D (GPRC5D), signaling lymphocytic activation molecule family member 7 (SLAMF7), and CD38, among others. CAR T cells targeting these antigens, alone or in combination with anti-BCMA approaches, appear to be highly promising as they move from preclinical studies to early phase clinical trials. This review summarizes the current data with novel CAR T cell targets beyond BCMA that have the potential to enter the treatment landscape in the near future.

Since its first approval by the FDA in 2017, tremendous progress has been made in chimeric antigen receptor (CAR) T cell therapy, the adoptive transfer of engineered, CAR-expressing T lymphocyte. CAR T cells are all composed of three main elements: an extracellular antigen-binding domain, an intracellular signaling domain responsible for T cell activation, and a hinge that joins these two domains. Continuous improvement has been made in CARs, now in their fifth generation, particularly in the intracellular signaling domain responsible for T cell activation. CAR T cell therapy has revolutionized the treatment of hematologic malignancies. Nonetheless, the use of CAR T cell therapy for solid tumors has not attained comparable levels of success. Here we review the challenges in achieving effective CAR T cell therapy in solid tumors, and emerging CAR T cells that have shown great promise for non-small cell lung cancer (NSCLC). A growing number of clinical trials have been conducted to study the effect of CAR T cell therapy on NSCLC, targeting different types of surface antigens. They include epidermal growth factor receptor (EGFR), mesothelin (MSLN), prostate stem cell antigen (PSCA), and mucin 1 (MUC1). Potential new targets such as erythropoietin-producing hepatocellular carcinoma A2 (EphA2), tissue factor (TF), and protein tyrosine kinase 7 (PTK7) are currently under investigation in clinical trials. The challenges in developing CAR T for NSCLC therapy and other approaches for enhancing CAR T efficacy are discussed. Finally, we provide our perspective on imaging CAR T cell action by reviewing the two main radionuclide-based CAR T cell imaging techniques, the direct labeling of CAR T cells or indirect labeling via a reporter gene.

Abstract Light chain amyloidosis (AL) is a rare disease caused by the generalized deposition of misfolded free light chains. Patients with immunoglobulin M gammopathy (IgM) and indolent B-cell lymphoma such as marginal zone lymphoma (MZL) may in some instances develop AL amyloidosis. So far, CAR T cells for AL amyloidosis have only been reported utilizing the B cell maturation antigen as target, while CD19 has so far not been used in AL amyloidosis. We report the case of a 71-year-old male, diagnosed with systemic AL kappa amyloidosis and MZL, receiving third-generation CAR T cell therapy targeting CD19. Prior treatment included bendamustine/rituximab and cyclophosphamide/ dexamethasone with subsequent autologous stem cell transplantation. CAR T application was well tolerated despite heart and kidney amyloid manifestations, and only early low-grade procedure-specific toxicities were observed. A continuous decrease in IgM, kappa light chains and kappa-to-lambda light chain difference was observed in the patient from day + 30 on, resulting in a deep hematological response six months after treatment. In summary, we present a novel case of CAR T cell treatment with third generation CD19 directed infusion for AL amyloidosis with an underlying secretory active B cell lymphoma, showing that this is an effective treatment modality and can be applied to patients with subsequent AL amyloidosis.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the management of relapsed and refractory myeloma, with excellent outcomes and a tolerable safety profile. High dose chemotherapy with autologous hematopoietic stem cell transplantation (AHCT) is established as a mainstream of newly diagnosed multiple myeloma (NDMM) management in patients who are young and fit enough to tolerate such intensity. This standard was developed based on randomized trials comparing AHCT to chemotherapy in the era prior to novel agents. More recently, larger studies have primarily shown a progression free survival (PFS) benefit of upfront AHCT, rather than overall survival (OS) benefit. There is debate about the significance of this lack of OS, acknowledging the potential confounders of the chronic nature of the disease, study design and competing harms and benefits of exposure to AHCT. Indeed upfront AHCT may not be as uniquely beneficial as we once thought, and is not without risk. New quadruple-agent regimens are highly active and effective in achieving a deep response as quantified by measurable residual disease (MRD). The high dose chemotherapy administered with AHCT imposes a burden of short and long-term adverse effects, which may alter the disease course and patient’s ability to tolerate future therapies. Some high-risk subgroups may have a more valuable benefit from AHCT, though still ultimately suffer poor outcomes. When compared to the outcomes of CAR T cell therapy, the question of whether AHCT can or indeed should be deferred has become an important topic in the field. Deferring AHCT may be a personalized decision in patients who achieve MRD negativity, which is now well established as a key prognostic factor for PFS and OS. Reserving or re-administering AHCT at relapse is feasible in many cases and holds the promise of resetting the T cell compartment and opening up options for immune reengagement. It is likely that personalized MRD-guided decision making will shape how we sequence in the future, though more studies are required to delineate when this is safe and appropriate.

IntroductionChimeric Antigen Receptor (CAR) T cell therapy has demonstrated remarkable success in treating hematological malignancies. However, its efficacy against solid tumors, including cervical cancer, remains a challenge. Hypoxia, a common feature of the tumor microenvironment, profoundly impacts CAR T cell function, emphasizing the need to explore strategies targeting hypoxia-inducible factor-1α (HIF-1α).MethodsIn this study, we evaluated the effects of the HIF-1α inhibitor PX-478 on mesoCAR T cell function through in-silico and in vitro experiments. We conducted comprehensive analyses of HIF-1α expression in cervical cancer patients and examined the impact of PX-478 on T cell proliferation, cytokine production, cytotoxicity, and exhaustion markers.ResultsOur in-silico analyses revealed high expression of HIF-1α in cervical cancer patients, correlating with poor prognosis. PX-478 effectively reduced HIF-1α levels in T and HeLa cells. While PX-478 exhibited dose-dependent inhibition of antigen-nonspecific T and mesoCAR T cell proliferation, it had minimal impact on antigen-specific mesoCAR T cell proliferation. Notably, PX-478 significantly impaired the cytotoxic function of mesoCAR T cells and induced terminally exhausted T cells.DiscussionOur results underscore the significant potential and physiological relevance of the HIF-1α pathway in determining the fate and function of both T and CAR T cells. However, we recognize the imperative for further molecular investigations aimed at unraveling the intricate downstream targets associated with HIF-1α and its influence on antitumor immunity, particularly within the context of hypoxic tumors. These insights serve as a foundation for the careful development of combination therapies tailored to counter immunosuppressive pathways within hypoxic environments and fine-tune CAR T cell performance in the intricate tumor microenvironment.

Simple Summary: The specific mechanisms by which tumors acquire resistance to chimeric antigen receptor (CAR) T cell therapy are not completely understood. The aim of this study was to elucidate the complex interactions between tumor cells and CAR T cells targeting epithelial cell adhesion molecule (EpCAM) in a xenograft model of gastric cancer. Using whole-body CAR T cell imaging and single-cell multiomic analyses, we noticed that within resistant tumors, CAR T cells exhibited a tendency to proliferate, but they were largely dysfunctional, losing their ability to fight cancer effectively. Specifically, most CD8 T cells became exhausted within tumors, while CD4 T cells transformed into regulatory T cells that can dampen the immune response. Additionally, the resistant tumor cells had specific gene changes that could promote cancer growth and make the disease more challenging to cure. This research provides valuable information for understanding how tumors resist CAR T cell therapy and may guide future developments in cancer treatment. Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen that is frequently overexpressed in various carcinomas. We have developed chimeric antigen receptor (CAR) T cells specifically targeting EpCAM for the treatment of gastric cancer. This study sought to unravel the precise mechanisms by which tumors evade immune surveillance and develop resistance to CAR T cell therapy. Through a combination of whole-body CAR T cell imaging and single-cell multiomic analyses, we uncovered intricate interactions between tumors and tumor-infiltrating lymphocytes (TILs). In a gastric cancer model, tumor-infiltrating CD8 T cells exhibited both cytotoxic and exhausted phenotypes, while CD4 T cells were mainly regulatory T cells. A T cell receptor (TCR) clonal analysis provided evidence of CAR T cell proliferation and clonal expansion within resistant tumors, which was substantiated by whole-body CAR T cell imaging. Furthermore, single-cell transcriptomics showed that tumor cells in mice with refractory or relapsing outcomes were enriched for genes involved in major histocompatibility complex (MHC) and antigen presentation pathways, interferon-γ and interferon-α responses, mitochondrial activities, and a set of genes (e.g., CD74, IDO1, IFI27) linked to tumor progression and unfavorable disease prognoses. This research highlights an approach that combines imaging and multiomic methodologies to concurrently characterize the evolution of tumors and the differentiation of CAR T cells. [ABSTRACT FROM AUTHOR]

Purpose of Review: To review the current and future role of cardiovascular magnetic resonance (CMR) assessment of immunotherapy cardiotoxicity. Recent Findings: In patients who suffer from immune checkpoint inhibitor (ICI) myocarditis, pathologic CMR findings, including myocardial edema, reduced left ventricular ejection fraction (LVEF), late gadolinium enhancement (i.e., fibrosis and/or necrosis), and myocardial strain, are mostly subtle, but fulminant courses have been described. Individual cases of cardiotoxicity in chimeric antigen receptor (CAR) T cell therapy have also already been documented, but there are currently no studies addressing the role of CMR in CAR T cell therapy. There are also classes of immunotherapies for which no cases of cardiotoxicity are known yet, such as cytokines or adjuvants. Summary: Together with patient symptoms, laboratory markers, electrocardiogram, and echocardiography, CMR is of high value in the diagnostic workup of immunotherapy-associated myocarditis in hemodynamically stable patients, according to recent guidelines. Additionally, quantitative strain analysis and T1 relaxation times with CMR can aid in assessing disease severity, prognosis, and patient outcomes with ICI-associated myocarditis. Future CMR studies on cardiotoxicity in CAR T cell therapy are needed. [ABSTRACT FROM AUTHOR]

Purpose of Review: To outline the spectrum of neurotoxicity seen with approved immunotherapies and in pivotal clinical trials including immune checkpoint inhibitors, chimeric antigen receptor T-cell therapy, vaccine therapy, and oncolytic viruses. Recent Findings: There has been an exponential growth in new immunotherapies, which has transformed the landscape of oncology treatment. With more widespread use of cancer immunotherapies, there have also been advances in characterization of its associated neurotoxicity, research into potential underlying mechanisms, and development of management guidelines. Increasingly, there is also mounting interest in long-term neurologic sequelae. Summary: Neurologic complications of immunotherapy can impact every aspect of the central and peripheral nervous system. Early recognition and treatment are critical. Expanding indications for immunotherapy to solid and CNS tumors has led to new challenges, such as how to reliably distinguish neurotoxicity from disease progression. Our evolving understanding of immunotherapy neurotoxicity highlights important areas for future research and the need for novel immunomodulatory therapeutics. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy is a revolutionary form of immunotherapy that has proven to be efficacious in the treatment of many hematologic cancers. CARs are modified T lymphocytes that express an artificial receptor specific to a tumor-associated antigen. These engineered cells are then reintroduced to upregulate the host immune responses and eradicate malignant cells. While the use of CAR T cell therapy is rapidly expanding, little is known about how common side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) present radiographically. Here we provide a comprehensive review of how side effects present in different organ systems and how they can be optimally imaged. Early and accurate recognition of the radiographic presentation of these side effects is critical to the practicing radiologist and their patients so that these side effects can be promptly identified and treated. [ABSTRACT FROM AUTHOR]

Gene therapy, recently frequently investigated, is an alternative treatment method that introduces therapeutic genes into a cancer cell or tissue to cause cell death or slow down the growth of the cancer. This treatment has various strategies such as therapeutic gene activation or silencing of unwanted or defective genes; therefore a wide variety of genes and viral or nonviral vectors are being used in studies. Gene therapy strategies in cancer can be classified as inhibition of oncogene activation, activation of tumor suppressor gene, immunotherapy, suicide gene therapy and antiangiogenic gene therapy. In this review, we explain gene therapy, gene therapy strategies in cancer, approved gene medicines for cancer treatment and future of gene therapy in cancer. Today gene therapy has not yet reached the level of replacing conventional therapies. However, with a better understanding of the mechanism of cancer to determine the right treatment and target, in the future gene therapy, used as monotherapy or in combination with another existing treatment options, is likely to be used as a new medical procedure that will make cancer a controllable disease. [ABSTRACT FROM AUTHOR]

Light chain amyloidosis (AL) is a rare disease caused by the generalized deposition of misfolded free light chains. Patients with immunoglobulin M gammopathy (IgM) and indolent B-cell lymphoma such as marginal zone lymphoma (MZL) may in some instances develop AL amyloidosis. So far, CAR T cells for AL amyloidosis have only been reported utilizing the B cell maturation antigen as target, while CD19 has so far not been used in AL amyloidosis. We report the case of a 71-year-old male, diagnosed with systemic AL kappa amyloidosis and MZL, receiving third-generation CAR T cell therapy targeting CD19. Prior treatment included bendamustine/rituximab and cyclophosphamide/ dexamethasone with subsequent autologous stem cell transplantation. CAR T application was well tolerated despite heart and kidney amyloid manifestations, and only early low-grade procedure-specific toxicities were observed. A continuous decrease in IgM, kappa light chains and kappa-to-lambda light chain difference was observed in the patient from day + 30 on, resulting in a deep hematological response six months after treatment. In summary, we present a novel case of CAR T cell treatment with third generation CD19 directed infusion for AL amyloidosis with an underlying secretory active B cell lymphoma, showing that this is an effective treatment modality and can be applied to patients with subsequent AL amyloidosis. [ABSTRACT FROM AUTHOR]

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are chimeric antigen receptor (CAR) T-cell therapies used to treat adult patients with relapsed or refractory follicular lymphoma (rrFL) after two or more lines of systemic therapy. In the absence of head-to-head clinical trials, this study aimed to compare the efficacy, safety, and cost of axi-cel and tisa-cel in the treatment of rrFL after at least two lines of treatment. Overall response rate (ORR) and safety signals were compared using reporting odds ratios (RORs) with 95% confidence intervals (CIs) at p < 0.05. Progression-free survival (PFS), duration of response (DoR), and overall survival (OS) were compared using the Kaplan?Meier method with a log-rank test. Cost and cost-minimization analyses of drug acquisition, drug administration, serious adverse events (AEs), and relapsed management were calculated. Costs were extracted from the IBM-Micromedex Red Book, Centers for Medicare and Medicaid Services, and existing literature. Statistical analyses were conducted using Microsoft Excel and R version 4.0.5. No statistically significant differences were observed between axi-cel and tisa-cel in terms of ORR, DoR, and OS (p > 0.05). PFS was significantly better with tisa-cel (p < 0.05). Axi-cel was significantly associated with higher incidences of CRS, neurologic events, and grade 3–4 AEs than tisa-cel (ROR > 1, p < 0.05). Axi-cel and tisa-cel cost $512,021 and $450,885 per patient, respectively, resulting in savings of US$61,136 with tisa-cel over axi-cel. Tisa-cel appears to have a better safety profile, fewer serious AEs, lower mortality rate, and lower cost than axi-cel. Key points: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are recently approved gene therapies for treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of treatment. To date, no data were available to understand the differences in their efficacy, safety, and financial impact. This study compared the two treatments based on pivotal clinical trials. The results indicated that tisa-cel is a superior treatment over axi-cel, with better efficacy, fewer serious adverse events, and less economic burden. [ABSTRACT FROM AUTHOR]

Abstract CAR T cell-based therapies have revolutionized the treatment of hematological malignancies such as leukemia and lymphoma within the last years. In contrast to the success in hematological cancers, the treatment of solid tumors with CAR T cells is still a major challenge in the field and attempts to overcome these hurdles have not been successful yet. Radiation therapy is used for management of various malignancies for decades and its therapeutic role ranges from local therapy to a priming agent in cancer immunotherapy. Combinations of radiation with immune checkpoint inhibitors have already proven successful in clinical trials. Therefore, a combination of radiation therapy may have the potential to overcome the current limitations of CAR T cell therapy in solid tumor entities. So far, only limited research was conducted in the area of CAR T cells and radiation. In this review we will discuss the potential and risks of such a combination in the treatment of cancer patients.

Standard-of-care treatment for Glioblastoma Multiforme (GBM) is comprised of surgery and adjuvant chemoradiation. Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated disease-modifying activity in GBM and holds great promise. Radiation, a standard-of-care treatment for GBM, has well-known immunomodulatory properties and may overcome the immunosuppressive tumor microenvironment (TME); however, radiation dose optimization and integration with CAR T cell therapy is not well defined. Murine immunocompetent models of GBM were treated with titrated doses of stereotactic radiosurgery (SRS) of 5, 10, and 20 Gray (Gy), and the TME was analyzed using Nanostring. A conditioning dose of 10 Gy was determined based on tumor growth kinetics and gene expression changes in the TME. We demonstrate that a conditioning dose of 10 Gy activates innate and adaptive immune cells in the TME. Mice treated with 10 Gy in combination with mCAR T cells demonstrated enhanced antitumor activity and superior memory responses to rechallenge with IL13Rα2-positive tumors. Furthermore, 10 Gy plus mCAR T cells also protected against IL13Rα2-negative tumors through a mechanism that was, in part, c-GAS-STING pathway-dependent. Together, these findings support combination conditioning with low-dose 10 Gy radiation in combination with mCAR T cells as a therapeutic strategy for GBM.

Background: Chimeric Antigen Receptor (CAR) T cell therapies are innovative treatments against hematological malignancies, with increasing therapeutic indications. Despite their great efficacy, these therapies are hampered by high rates of neurotoxicity (immune effector cell–associated neurotoxicity (ICANS)). In the past few years, several risk factors have been associated with ICANS and grouped together in the attempt to build validated models able to predict neurologic complications. However, little is known about pre-existing neurologic conditions possibly related to the development of neurotoxicity. Methods and results: In our case series, including sixteen consecutive patients treated with CAR T cells, we observed that (i) neurotoxicity only occurred in the two patients who presented subtle clinical signs of frontal lobe impairment at baseline and (ii) neurologic manifestations of ICANS consisted of language disturbances and cortical frontal myoclonus, which were both manifestations of a frontal predominant dysfunction. Discussion: Based on our experience, we suggest that a pre-existing frontal lobe impairment, even if at a subclinical level, may eventually drive to ICANS, which in turn shows symptoms compatible with a frontal encephalopathy. It is remarkable that this focal neurotoxicity involved the same CNS regions that were responsible of subtle neurological signs at baseline. Future studies on larger numbers of patients are needed to confirm the possible role of baseline frontal lobe dysfunction as a predictor of ICANS, in order to enhance efforts to safely deliver CAR T cell therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is the leading cause of cancer related mortality and morbidity in the United States and worldwide. The advent of Immunotherapy has significantly improved lung cancer prognosis. However, there is a huge unmet need for novel agents, as a significant number of patients do not have durable responses to immunotherapy. This review article highlights two such novel techniques—Chimeric antigen receptor (CAR) T-cell therapy and Tumor-infiltrating lymphocyte (TIL) therapy. Both these techniques utilize a patient's own immune cells to fight against tumors. While CAR T-cell therapy requires genetic modification of a patient's T cells to express receptors that can recognize and attack tumor cells rapidly, TILs involves extraction of immune cells from tumors and their proliferation in a laboratory before being infused back to the patient. Both these techniques are currently used in a clinical trial setting only. In this review, we discuss the limitations and future directions and potential for both these treatment strategies. Lung cancer is a leading cause of morbidity and mortality in the United States and worldwide. The introduction of immune checkpoint inhibitors has led to a marked improvement in the outcomes of lung cancer patients. Despite these advances, there is a huge unmet need for therapeutic options in patients who are not candidates for targeted or immunotherapy or those who progress after first-line treatment. With its high mutational burden, lung cancer appears to be an attractive target for novel personalized treatment approaches. In this review, we provide an overview of two adoptive cell therapy approaches–chimeric antigen receptors (CAR) T-cell therapy and Tumor-infiltrating lymphocytes (TILs) in lung cancer with an emphasis on current challenges and future perspectives. While both these therapies are still in the early phases of development in lung cancer and need more refinement, they harbor the potential to be effective treatment options for this group of patients with otherwise poor prognoses. [ABSTRACT FROM AUTHOR]