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Immunotherapy is an effective way to mobilize the body's own immune system to confront tumor cells. However, the efficacy of immunotherapy is affected by tumor heterogeneity, and the low therapeutic response to immunotherapy may lead to negative outcomes, which reinforces the urgency for early benefit predictors. Evaluating the infiltration of immune cells in solid tumors and metabolism changes of tumors provide potential response targets for monitoring immune response. Non-invasive imaging identifying prognostic biomarkers can select the beneficiaries of targeted immunotherapy from non-responses. Quantitative biomarkers may eventually improve the cancer management, help customize individual treatment plans and predict the treatment outcomes. In this review, we summarize the non-invasive optical molecular imaging methods for monitoring immunotherapy. With the combination of imaging and immunotherapy, the prediction of immunotherapy response may promote the development of precision medicine.

Background: SV-BR-1-GM is a GM-CSF transfected breast cancer cell line, exceptional for having antigen-presenting capability and expressing both HLA I and II. The parent cell line, SV-BR-1, was derived from a patient with grade II (moderately differentiated) breast cancer. We report molecular characterization of SV-BR-1-GM, noting it retains features of a grade II tumor, and report enhanced disease control in patients with grade I or II breast cancer.Methods: SV-BR-1 and SV-BR-1-GM were characterized molecularly using RNAseq and proteomic analyses. We treated 23 evaluable patients with recurrent and/or metastatic breast cancer refractory to standard therapy. The SV-BR-1-GM regimen included cyclophosphamide 300 mg/m2 2-3d prior to intradermal injection of SV-BR-1-GM (20-40x106 cells divided into 4 sites) and IFNα into the inoculation sites (10,000 IU/site) about 48 and 96 hours subsequently. Cycles were q2 weeks x3 then qmo x 3 (clinical trial NCT03066947). Eleven patients were treated with the above regimen in combination with a PD-1 inhibitor (pembrolizumab or INCMGA00012) (clinical trial NCT03328026). Disease response was evaluated radiographically q3 mo and as clinically indicated. Results: To estimate the tumor grade represented by the SV-BR-1-GM cell line, we developed a score we refer to as Relative Molecular Grade (RMG). SV-BR-1-GM is most similar to the MDA-MB-468 cell line (RMG of 52.1), which was classified as Basal A phenotype. Basal A cancers are less aggressive than Basal B but more aggressive than Luminal, suggesting that SV-BR-1-GM may have retained features of a grade II breast cancer. We also noted that SV-BR-1-GM expresses both Class I (HLA-A, B & C) and Class II (HLA-DR and -DP) molecules, and that the HLA-DR expression is enhanced by treatment with IFNγ. SV-BR-1-GM expressed 31 genes which are overexpressed in breast cancer, 8 cancer-testis antigens and 3 genes expressed in breast tissue. In 30 patients treated with the SV-BR-1-GM regimen (19 with the SV-BR-1-GM regimen alone, 4 who began on the SV-BR-1-GM regimen and transitioned to combination with a PD-1i, and 7 with combination therapy alone) there were 7 with grade II breast cancer and 1 with grade I breast cancer (Table). These patients were heavily pre-treated with an average of 10 prior regimens. While only one patient with grade III cancer showed disease control, 75% of the patients with grade I or II tumors showed disease control. Patients remained on study for up to 259 days.Conclusions: SV-BR-1-GM appears to retain characteristics of a moderately differentiated breast cancer, expresses multiple potential tumor antigens, and can elicit disease control especially in patients with grade I and II breast cancer. TablePatients with Grade I/II TumorsCharacteristicSV-BR-1-GM Regimen Alone(n=6)SV-BR-1-GM Regimen + PD-1i(n=3)All Patients(n=8)Age64 ± 767 ± 465 ± 7Mean Prior Systemic Regimens6 (range 1-20)15 (range 14-15)10 (range 1-20)% ER/PR +80%100%86%% Her2/neu +0%33%14%% Triple Negative20%0%14%Delayed-type Hypersensitivity83%100%88%Disease Control Rate*67%100%75%Days on Study (Range)94 (32-181)189 (133-259)141 (32-259)•Includes CR, PR, SD (including minor responses and mixed responses) Citation Format: William Williams, Shaker R Dakhil, Carmen Calfa, Jarrod P Holmes, Saveri Bhattacharya, Jason Lukas, Elizabeth Tan-Chiu, George E Peoples, Vivek G Sunkari, Markus D Lacher, Charles L Wiseman. Response to a modified whole tumor cell targeted immunotherapy in patients with advanced breast cancer correlates with tumor grade [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-20.

PD-L1 and PD-1 inhibitors are being increasingly used to treat a variety of nonmelanoma skin cancers (NMSCs). This systematic review summarizes PD-L1 expression in NMSCs and determines its use for prognosis using targeted immunotherapy. A primary search of peer-reviewed English-language medical literature was conducted for studies on PD-L1 tumor expression in biopsied or excised NMSCs. Fifty-nine articles met criteria for inclusion. PD-L1 expression in advanced NMSCs ranged from 22%-89% for basal cell carcinomas, 42%-50% for Merkel cell carcinomas, and 26%-100% for squamous cell carcinomas. Study limitations included clone heterogeneity across studies, complicating comparison of PD-L1 expression. Differences were also noted in the selection of tumor reactivity threshold. We conclude that there is insufficient evidence to determine the prognostic significance of PD-L1 expression in NMSCs as a whole, but this remains a promising area. More investigation into the role of tumor PD-L1 as a biomarker for predicting clinical response to PD-L1 and PD-1 inhibitors in NMSCs is needed.

This is an overview of current problematics regarding the role of tumor infiltrating lymphocytes (TILs) in malignant melanomas. Various and often conflicting data have been published, correlating tumor type, stage, prognosis, as well as sex and age of patients. This is partly due to heterogeneity in scaling systems and unstandardized TILs grading but also due to changes of tumor-host interactions. Melanomas are an immunologically heterogeneous group with variability of TILs, where distinct gene expression patterns were found in tumors with absent, and/or non- brisk TIL grade versus brisk TIL grade. However, the presence of TILs alone appears to be inadequate for implicating them as immunologically functional. Further characterisation of TIL phenotype and function is warranted. This especially concerns, evaluation of TILs of the suppressor phenotype but rather than as a prognostic factor, more for prediction of targeted immunotherapy.

Chikungunya virus (CHIKV) is the most common mosquito-borne Alphavirus infecting humans worldwide. Up to date, there are no antiviral treatments or vaccines approved to treat or prevent CHIKV for which treatments remain symptomatic based on clinical manifestations. Hence, designing effective therapies to either prevent or treat CHIKV infection is of paramount importance. Interestingly, monoclonal antibodies (mAbs) are known to be significantly important in mediating protective immunity in CHIV infection. During the last decades, numerous animal studies have reported the protective and prophylactic efficacy of human and mouse anti-CHIKV mAbs isolated from convalescent patients. However, the therapeutic benefits of these anti-CHIKV mAbs can be limited by multiple factors. Thus, it becomes pertinent to better understand the CHIKV infection dynamics, mitigate the undesired mAbs-associated effects and improve therapies. In this review, we critically discuss CHIKV antiviral infectious mechanisms and address how the improved understanding of the latter may pave the way to better targeted immunotherapies.

Cancer immunotherapeutic strategies have shifted the focus of cancer treatment from eradicating the tumor cell by conventional cytotoxic chemotherapy, to educating the immune system to eliminate tumor, thereby preventing the recurrence of cancer. The understanding of tumor microenvironment and its components which generate an immunosuppressive environment is critical in further developing efficient immunotherapies. In this review, we have classified the current immunotherapies based on their effect in modulating the tumor microenvironment. Additionally, we propose the inclusion of nanotechnology and tissue engineering approaches, which provide unique strategies to enhance the therapeutic efficacy and could lead to developing nano/engineered immunotherapies for improved clinical outcomes. Specifically, we focus on criteria for designing nano/engineered immunotherapies and discuss targeted delivery strategies that can optimize the bioavailability of immunotherapies and, in turn, improve the therapeutic outcomes in the treatment of cancer. Several strategies aimed to exploit the therapeutic benefits of immunotherapy are based on alterations of the complex immunosuppressive tumor microenvironment. Such targeted approaches have also been significantly improved by various design criteria based on the concepts of nanotechnology and tissue engineering. The properties of specific targeting, controlled release, and ability to attain enhanced therapeutic effects with low doses conferred by these approaches have immensely helped to surmount the side effects and off-target issues of existing methods. Incorporation of these design criteria while developing various carrier systems for targeted immunotherapy would certainly enhance their clinical translation potential, eventually augmenting anti-tumor responses. Modulation of tumor microenvironment with strategies discussed in this review will provide additional opportunities to improve cancer immunotherapy, especially in challenging diseases such as pancreatic and brain tumors. Various design attributes with targeted systems would provide numerous advantages, widening the scope of clinical translation and benefits to cancer patients.

Programmed cell death protein-1-targeted immunotherapy has shown promising results in phase II studies of hepatocellular carcinoma.To evaluate safety and efficacy of nivolumab and pembrolizumab in an international, multicentre, real-world cohort of patients with advanced hepatocellular carcinoma.Sixty-five patients treated with nivolumab (n = 34) or pembrolizumab (n = 31) between July 10, 2015 and December 31, 2018 (data cut-off) across six centres in Austria and Germany were retrospectively analysed.Child-Pugh class A/B/C was 32 (49%)/28 (43%)/5 (8%). Immunotherapy was used as systemic first-/second-/third-/fourth-line treatment in 9 (14%)/27 (42%)/26 (40%)/3 (5%) patients. Fifty-four patients had at least one follow-up imaging and were, therefore, available for radiological response assessment. The overall response and disease control rates were 12% and 49% respectively. Of 52 evaluable patients, four (8%) had hyperprogressive disease. Median time to progression was 5.5 (95% CI, 3.5-7.4) months, median progression-free survival was 4.6 (95% CI, 3.0-6.2) months, and median overall survival was 11.0 (95% CI, 8.2-13.8) months. Most common adverse events were infections (n = 7), rash (n = 6), pruritus (n = 3), fatigue (n = 3), diarrhoea (n = 3) and hepatitis (n = 3). Efficacy and safety results were comparable between Child-Pugh A and B patients; however, median overall survival (OS) was shorter in Child-Pugh B patients (16.7 vs 8.6 months; P = 0.065). There was no difference in terms of efficacy and adverse events between patients who received immunotherapy as first-/second-line and third-/fourth-line respectively.Programmed cell death protein-1-targeted immunotherapy with nivolumab or pembrolizumab showed promising efficacy and safety in patients with advanced hepatocellular carcinoma, including subjects with Child-Pugh stage B and patients with intensive pretreatment.

Many transplant recipients die with functional transplant grafts. Immune-related morbidity and mortality due to conventional systemic immunosuppression continue being the major barrier against long-term success of solid organ transplantation including liver transplantation (LT). Targeted immunotherapy is urgently needed.

Autoimmune or infectious diseases often instigate the undesirable damages to tissues or organs to trigger immune-related diseases, which involve plenty of immune cells, pathogens and autoantibodies. Nanomedicine has a great potential in modulating immune system. Particularly, biomimetic nanomodulators can be designed for prevention, diagnosis and therapy to achieve a better targeted immunotherapy. With the development of materials science and bioengineering, a wide range of membrane-coated nanomodulators are available. Herein, we summarize recent advancements of bioinspired membrane-coated nanoplatform for systemic protection against immune-related diseases including autoimmune and infectious diseases. We also rethink the challenges or limitations in the progress of the therapeutic nanoplatform, and discuss the further application of the nanomodulators in the view of translational medicine for combating immune-related diseases.

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive memory decline, histopathological lesions such as amyloid β plaques and neurofibrillary tangles, and neuroinflammation driven by glial cells. Microglia, the innate immune cells of the brain, dynamically survey their environment for signs of infection and cell damage. Although our understanding of microglia and their modes of activation has expanded in recent years, their role in AD is still not completely understood. Broad range of microglia phenotypes, from neuroinflammatory to neuroprotective, found in neurodegenerative diseases make their role difficult to discern. In this review, we summarize activities of microglia in healthy and AD brains and their possible role during immunotherapy targeted against pathological tau proteins.

BACKGROUND MDNA55 is an IL4R-targeted toxin in development for treatment of recurrent glioblastoma (rGBM). MDNA55 binds to IL4R expressed by tumor cells and non-malignant cells of the tumor microenvironment. METHOD MDNA55-05 was an open-label, single-arm study of MDNA55 delivered by CED as a single treatment in patients with 1st or 2nd recurrence following de novo GBM, IDH wild type status and not indicated for resection at relapse. Dose volumes (up to 60mL) and concentration of MDNA55 (1.5 to 9.0 μg/mL) were studied. RESULTS MDNA55 showed an acceptable safety profile at all doses tested. Median OS (mOS) amongst all subjects was 11.9 months, OS-24 was 20%, and PFS-12 was 27%. Among subjects expressing high levels of IL4R (irrespective of MDNA55 dose) and low levels of IL4R expression administered high dose (≥ 180μg) of MDNA55 (IL4Rhi + IL4Rlo/hd), mOS further improved to 14.0 months with OS-24 of 20%. Unmethylated MGMT promoter status did not affect MDNA55 treatment outcomes. In the IL4Rhi + IL4Rlo/hd population (N=17), mOS was 14.9 months with OS-24 of 22%. Following treatment with high concentrations of MDNA55 (6.0 or 9.0 μg/mL), transient (median of 3 cycles) low dose Avastin (5mg/kg q2w or 7.5mg/kg q3w) was used for symptom control and steroid sparring. Among these subjects, mOS amongst all comers (N=9) and the IL4Rhi + IL4Rlo/hd group (N=8) increased to 21.8 and 18.6 months with OS-24 of 44% and 38%, respectively. CONCLUSIONS MDNA55 shows potential to benefit all rGBM patients treated at high dose irrespective of IL4R expression. In the 1:1 randomized Phase 3 trial, the study will enrol two-thirds of subjects in the SOC arm from a matched external control arm. Unlike conventional RCTs, the hybrid design sets a new precedent for GBM trials, allowing robust OS analysis while significantly reducing the number of subjects randomized to SOC arm.

Melanoma has increased in incidence worldwide prompting investigators to search for new biomarkers for targeted immunotherapy of this disease. Placenta specific 1 (PLAC1) is a new member of cancer-testis antigens with widespread expression in many types of cancer. Here, we aimed to study for the first time the expression pattern of PLAC1 in skin cancer samples including cutaneous melanoma, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) in comparison to normal skin and nevus tissues and potential therapeutic effect of anti-PLAC1 antibody in melanoma cancer cell linesPolyclonal and monoclonal antibodies were applied for immunohistochemical profiling of PLAC1 expression using tissue microarray. The cytotoxic action of anti-PLAC1 antibody alone or as an antibody drug conjugate (with anti-neoplastic agent SN38) was investigated in melanoma cell lines.We observed that 100% (39 of 39) of melanoma tissues highly expressed PLAC1 with both cytoplasmic and surface expression pattern. Investigation of PLAC1 expression in BCC (Our findings re-inforce the concept of re-expression of embryonic/placental tissue antigens in cancer and highlight the possibility of melanoma targeted therapy by employing anti-PLAC1 antibodies. The data presented here should lead to the future research on targeted immunotherapy of patients with melanoma.

Generalized pustular psoriasis (GPP) is a rare, inflammatory skin disease characterized by recurrent flares of pustulation accompanied by systemic symptoms. Due to its acuteness, sufficient diagnosis and treatment are essential, but often face challenges. We recently overviewed various treatment options of GPP utilizing established therapies in psoriasis vulgaris (PsO). Although there is a pathogenic relation to PsO, more and more evidence suggests a predominant involvement of the innate immune system in GPP. Recent discoveries on the genetic background of GPP with underlying mutations in IL36RN, CARD14, AP1S3 and SERPINA3 contributed to a better understanding of the pathogenesis and provide major opportunities in the development of innovative, targeted therapies. The proposed umbrella term "autoinflammatory keratinization diseases" (AIKD) helps to categorize this heterogeneous disease. Finally, we address the problem of insufficient standardized assessment tools and propose a reproducible scoring system also capturing the systemic features of GPP. In summary, GPP is a prototype disease to demonstrate both obstacles and progress in dermatology-currently insufficient definition and diagnostic tools on the one hand side, yet major advances in dissecting disease heterogeneity, opportunities for novel diagnostic techniques and therapeutic decision-making based on molecular events on the other side.

B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as well as BCMA-targeted immunotherapeutic agents in different stages of clinical development.

Overexpression of CD30 has been reported on the surface of some T-cell lymphomas, especially on Hodgkin's lymphoma (HL) and anaplastic large cell lymphoma (ALCL). CD30 targeted immunotherapy has good clinical therapy response. We have produced a novel antibody drug conjugates (ADCs)-anti-CD30-LDM, which shows attractive tumour-targeting capability and extremely potent antitumor efficacy. To further investigate biological characteristics and promote clinical translation of anti-CD30-LDM, we constructed a radiolabeled

Background:Improved survival with gemtuzumab ozogamicin (GO) in some people with acute myeloid leukemia has validated CD33 as immunotherapeutic target and sparked interested in developing new, highly potent CD33-directed therapeutics. As a limitation of this treatment strategy, CD33 expression on maturing and mature myeloid cells causes significant on-target, off-leukemia effects. Toxicity of CD33-targeted immunotherapy should be minimal in the presence of normal hematopoietic stem and progenitor cells (HSPCs) engineered to lack CD33 variants recognized by therapeutic antibodies. Indeed, very recent studies have shown that CRISPR/Cas9 with a single guide RNA (gRNA) designed to target the CD33coding region reduces display of CD33 and protects engineered cells from CD33 CAR T-cells. However, this approach resulted in low levels of CD33disruption in vivoand off-target activity. We therefore developed an approach in which the Cas9 protein is complexed with two synthetic gRNAs for precise excision of the intervening sequence (i.e. more controlled genome editing than what can be accomplished with a single gRNA). We directed these two gRNAs to intronic sequences for precise excision of exon 2, which encodes the V-set domain of CD33 that is recognized by all current CD33 therapeutics including GO. This approach eliminates exonic indels and protects engineered cells from CD33-targeted immunotherapy while maintaining expression of an exon 2-free variant of CD33 (CD33∆E2), which has previously been identified as natural isoform in human HSPCs. Methods: We used human myeloid ML-1 cells and human fetal liver CD34+ HSPCs for CRISPR/Cas9 editing, which was carried out by electroporation of purified Cas9 protein complexed with synthetic gRNAs. In vitro cytotoxicity assays were performed to test sensitivity to GO and the CD33/CD3 bispecific antibody AMG 330.For in vivoassessment of engineered HSPCs, NSG neonate mice were infused with 6.0x105human CD34+ cells, and peripheral blood analyzed biweekly for 14 weeks. Results:Delivery of Cas9/sgRNA ribonucleoproteins (RNPs) in ML-1 cells resulted in exon 2 deletion and time-dependent reduction in cell surface display of full-length CD33 (CD33FL). Pure populations of CD33∆E2cells were generated via single-cell cloning. These sublines lacked surface display of CD33FLbut, instead, expressed increased levels of the CD33∆E2transcript. CD33∆E2ML-1 cells were completely resistant to GO and AMG 330, whereas wild-type ML-1 cells were highly sensitive to these two drugs. Consistent with the findings in ML-1 cells, delivery of CRISPR/Cas9 RNPs to human fetal liver CD34+ HSPCs resulted in the expected CD33exon 2 deletion and decreased CD33FLsurface expression, while it did not impact the distribution of colony-forming cellsand only minimally reduced colony-forming potential. In NSG mouse xenotransplantation experiments, we found these CD33∆E2human CD34+ HSPCs to have comparable engraftment and multilineage differentiation potential relative to HSPCs expressing CD33FL(Fig. 1A). As expected, CD33FLexpression was substantially reduced in peripheral blood monocytes from CD33∆E2 HSPC-engrafted animals (Fig. 1B). In addition, robust engraftment of CD33∆E2 -engineered HSPCs in bone marrow was demonstrated by over 50% biallelic CD33exon 2 deletion at time of necropsy from colony-forming cells analysis (Fig. 1C). To determine if in vivodifferentiated myeloid CD33∆E2cells derived from infused human CD34+ HSPCs are indeed resistant to CD33-directed therapies, we treated mice with GO intravenously. GO administration reduced the number of circulating CD33FLCD14+ myeloid cells while leaving the number of CD33∆E2cells unaffected. Conclusion:These findings support a novel strategy in which CD33∆E2-engineeredHSPCs are used to widen the therapeutic window of CD33-directed immunotherapies. Such cells could be envisioned for people at risk for the need of CD33-immunotherapy, e.g. AML patients in remission (where CD33-immunotherapy could be used to prevent/treat relapse) or, pre-emptively, for people with genetic AML-predisposition syndromes (such that CD33-targeted immunotherapy could be given safely if AML occurred). With this potential, further development of CD33∆E2-engineered HSPCs toward clinical application is warranted. Disclosures Walter: Amphivena Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Aptevo Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Covagen AG: Consultancy, Other: Clinical Trial Support, Research Funding; Actinium Pharmaceuticals, Inc: Other: Clinical Trial support , Research Funding; Amgen Inc: Other: Clinical Trial Support, Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer, Inc: Consultancy; Seattle Genetics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding. Kiem:Magenta: Consultancy; Homology Medicine: Consultancy; Rocket Pharmaceuticals: Consultancy.

Animal models used to evaluate efficacies of immune checkpoint inhibitors are insufficient or inaccurate. We thus examined two xenograft models used for this purpose, with the aim of optimizing them. One method involves the use of peripheral blood mononuclear cells and cell line-derived xenografts (PBMCs-CDX model). For this model, we implanted human lung cancer cells into NOD-scid-IL2Rg−/− (NSI) mice, followed by injection of human PBMCs. The second method involves the use of hematopoietic stem and progenitor cells and CDX (HSPCs-CDX model). For this model, we first reconstituted the human immune system by transferring human CD34+ hematopoietic stem and progenitor cells (HSPCs-derived humanized model) and then transplanted human lung cancer cells. We found that the PBMCs-CDX model was more accurate in evaluating PD-L1/PD-1 targeted immunotherapies. In addition, it took only four weeks with the PBMCs-CDX model for efficacy evaluation, compared to 10–14 weeks with the HSPCs-CDX model. We then further established PBMCs-derived patient-derived xenografts (PDX) models, including an auto-PBMCs-PDX model using cancer and T cells from the same tumor, and applied them to assess the antitumor efficacies of anti-PD-L1 antibodies. We demonstrated that this PBMCs-derived PDX model was an invaluable tool to study the efficacies of PD-L1/PD-1 targeted cancer immunotherapies. Overall, we found our PBMCs-derived models to be excellent preclinical models for studying immune checkpoint inhibitors.

Neuroblastoma is a pediatric solid cancer of heterogeneous clinical behavior. The unique features of this type of cancer frequently hamper the process of determining clinical presentation and predicting therapy effectiveness. The tumor can spontaneously regress without treatment or actively develop and give rise to metastases despite aggressive multimodal therapy. In recent years, immunotherapy has become one of the most promising approaches to the treatment of neuroblastoma. Still, only one drug for targeted immunotherapy of neuroblastoma, chimeric monoclonal GD2-specific antibodies, is used in the clinic today, and its application has significant limitations. In this regard, the development of effective and safe GD2-targeted immunotherapies and analysis of other potential molecular targets for the treatment of neuroblastoma represents an important and topical task. The review summarizes biological characteristics of the origin and development of neuroblastoma and outlines molecular markers of neuroblastoma and modern immunotherapy approaches directed towards these markers.

In children, diffuse midline gliomas retain poor outcomes, failing to have a durable response to conventional therapies. Immunotherapies hold promise, with the integration of the host's immune system fundamental to their design. Here, we describe a novel genetically engineered immunocompetent model that incorporates interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-associated antigen, to evaluate the antitumor activity of IL13Rα2-CAR T cell and bispecific T cell engager (BiTE) therapies in preclinical studies. The RCAS-Tva delivery system was utilized to induce gliomagenesis through p53 loss and the constitutive expression of PDGFB and human IL13Rα2 in Nestin-Tva;p53fl/fl mice. Pups were injected with virus-producing DF1 cells, encoding either for RCAS-Cre and PDGFB+IL13Rα2 or RCAS-Cre and PDGFB. Kaplan-Meier survival curves established and compared tumor growth dynamics in both models. Tumor tissue was characterized through immunohistochemistry and H&E staining. Cell lines generated from tumor-bearing tissue were used for orthotopic injection and in vitro studies. Expression of PDGFB and IL13Rα2 was confirmed by flow cytometry and western blot. In both groups, de novo tumors developed without significant difference in median survival between RCAS:PDGFB (n=25, 40 days) and RCAS:PDGB+IL13Rα2 (n=32, 39 days). Tumors demonstrated characteristics of high-grade glioma such as infiltration, pseudopalisading necrosis, microvascular proliferation, high Ki-67 index, heterogenous IL13Rα2 expression, with notable presence of CD11b+ macrophages and low count of CD3+ T cells. Orthotopic tumors from developed cell lines were histologically similar to de novo tumors. Treatment of generated cell lines with IL13Rα2-targeting BiTE protein resulted in a loss of glioma cell viability and target-specific activation of T cells. Engineered de novo tumors possess histopathologic features common to diffused midline gliomas. IL13Rα2-positive cell lines derived from de novo tumors were responsive to targeted treatment, opening the opportunity for preclinical assessment of IL13Rα2-directed immunotherapies, with the potential for clinical translation.

BackgroundThe treatment of non-small cell lung cancer has been altered by immune-checkpoint therapy in the last 10 years. However, many patients still do not respond to it or, eventually, the disease progresses. One of the factors leading to primary resistance to ICI is the ”cold” tumor, characterized by the absence of T cell infiltration and not sufficiently primed for immune recognition. Here, we compared the neoantigen-based immunotherapy in two lung cancer cell lines: T cell-inflamed ASB-XIV and non-T cell-inflamed LLC1.MethodsWhole-exome and RNA sequencing were performed to identify neoantigens. First, MHC binding scores of expressed mutated peptides (FPKM>1) were estimated to select candidate neoantigens. Next, the immunogenicity of predicted mutated peptides was investigated. Then, the anti-tumor effect of immunogenic mutated peptides was accessed. Finally, immunosuppressive molecules in the non-T cell inflamed tumor microenvironment were investigated and targeted for effective treatment.ResultsInflamed ASB-XIV tumors were sensitive to ICI, while non-inflamed LCC1 tumors were resistant to ICI. Using ASB-XIV-specific CTLs, we screened the panel of candidate neoantigen peptides and identified Phf3 N1867K mutated peptide as neoepitope. Mutated Phf3 peptide-pulsed DCs induced peptide-specific CD8+ T cells and inhibited the ASB-XIV tumor growth in the prophylactic and therapeutic setting. Furthermore, adoptive transfer of mPhf3-specific CTLs also eradicated the ASB-XIV tumors. In the case of LLC1, twenty-five out of 132 short mutated peptides induced peptide-specific CD8+ T cell response, but they could not inhibit the LLC1 tumor growth. DC vaccines pulsed with long peptides (LP) induced both CD4+ and CD8+ T cell responses ex vivo. Of them, DC pulsed with LP82 partly delayed the LLC1 growth in vivo. By RNA-Seq, CD38 was highly expressed in LLC1. Thereby, an anti-CD38 antibody was administered in LLC1-bearing mice immunized with DC pulsed with LP82. The tumor growth was suppressed in the combination treatment, partly because CD38 blockade decreased regulatory T cells in the tumor.ConclusionsResponses to neoantigen-targeted immunotherapy preferentially observed in T cell-inflamed tumors. Regulation of immunosuppressive tumor microenvironment is required to make neoantigen-targeted immunotherapy effective in non-inflamed tumors.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death. Low response rate, acquired resistance, severe side effects, highly desmoplastic and immunosuppressive microenvironment have limited the clinical outcomes of immunotherapy in PDAC. To overcome these hurdles, we set to design a novel immunotherapy that would be safe, efficacious, and selective to PDAC. The failure of immunotherapies to yield clinical response in PDAC is partially attributed to the inefficient antigen presentation by dendritic cells (DC) which results in insufficient T cells stimulation despite their expression of tumor-associated antigens (TAA). DC have an important role in the initiation and regulation of the innate and adaptive arms of the immune system. By efficient presentation of antigens, DC elicit an antigen-specific immune response. Trp53R172H is among the most common TP53 mutations in human PDAC, and is known as one of PDAC TAA. Despite the poor clinical outcomes, longer survival time was observed in PDAC patients with tumors that express high number of TAA combined with an abundant presentation of CD8+ T cell. To that end, we designed a DC-targeted nanoparticle (NP) containing PDAC Trp53R172H TAA and immune potentiators, with the DC targeting moiety, mannose, that was covalently conjugated to the NP, to enhance TAA presentation on DC. This approach led to specific activation of T cells against PDAC's TAA. The therapeutic activity of the NP was evaluated in vitro by our newly established 3D PDAC spheroids model, which is composed of freshly isolated murine stromal cells, therefore, better imitates the complex microenvironment found in PDAC. Along with an in vivo PDAC model, we evaluated the safety profile and therapeutic efficacy of our NP. The NP proposed herein successfully activated splenocytes and induced a specific cytotoxic reaction against PDAC cells ex vivo, which may result in improved survival rate. Citation Format: Ron Kleiner, Daniella Vaskovich, Sabina Pozzi, Anat Eldar-Boock, Dikla Ben-Shushan, Helena Florindo, Ronit Satchi-Fainaro. Designing a dendritic cell-targeted immunotherapy for the treatment of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1746.

Background: Anti-programmed cell death protein-1 (PD-1) immunotherapy has shown promising outcomes in patients with advanced hepatocellular carcinoma(HCC). In practice anti-PD-1 drugs were mostly a part of combination therapy, especially in the Asia-Pacific region. We aimed to evaluate the effectiveness and safety of PD-1 inhibitors in combination therapies for HCC patients through real-world data. Methods: Between January 2018 and December 2019, patients with HCC who received anti-PD-1 immunotherapy were screened for eligibility. The primary efficacy endpoints included tumor response rate, overall survival(OS), and progression-free survival(PFS). Safety was assessed by immune-related adverse events (iAEs). Univariate and multivariate analyses were conducted to identified the risk factors of prognosis. Result: A total of 322 patients were included in our study. Anti-PD-1 immunotherapy was combined with locoregional interventional approaches (62.1%) and tyrosine kinase inhibitors TKIs (66.5%). The 3-, 6-, 12- and 18-month OS rate were 97.1%, 90.5%, 72.9%, and 57.3%, respectively. The 3-, 6-, 12- and 18-month PFS rate were 82.3%, 66.5%, 42.1%, and 30.3%, respectively. Overally, objective response rate (ORR) was 38.5%, and disease control rate (DCR) was 83.9%. The total rate of grade 3-4 treatment-related AEs was 5.9%, and laboratory-related AEs was 8.7%. Conclusion: PD-1-targeted immunotherapy as a part of a combination therapy, was a safe and effective treatment for intermediate and advanced HCC. Citation Format: Shaohua Li, Jie Mei, Qiaoxuan Wang, Wei Wei, Lianghe Lu, Jingwen Zou, Rongce Zhao, Zhixing Guo, Yihong Ling, Yuhua Wen, Wenping Lin, Lie Zheng, Minshan Chen, Rongping Guo. Role of programmed cell death protein-1 (PD-1)-targeted immunotherapy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 417.

Targeted immunotherapy has become the most promising approach for tumor patients. Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, can reverse immune suppression and release T cell activation. Nivolumab, a fully human immunoglobulin G4 PD-1 immune checkpoint inhibitor antibody, blocks PD-1 and promotes antitumor immunity, and it is effective for treating non-small-cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC) and other cancers. The present review summarizes the efficacy and current status of clinical trials of nivolumab and that enabled nivolumab to be investigated in patients.

Primary Sjogren's syndrome (pSS) is a typical multisystem disease, characterized by lymphocytic infiltration of the exocrine glands leading to glandular dysfunction. Multiple systemic manifestations occur in those of serious conditions, with different courses and outcomes. Its pathogenesis is complex, and its diagnosis and management are being constantly updated and improved. We have failed to have much progress in targeted immunotherapy for pSS, and as yet this is still based on empirical treatment. Many studies have tried to define pSS more accurately, to study its pathogenesis, to find effective treatment strategies, opening up new avenues for early diagnosis and precise management of pSS.

In recent years, oncolytic viruses (OVs) have emerged as a powerful, targeted immunotherapy with the identification of new viral vectors as well as genetically engineered viral payloads. Owing to t...

The multifactorial and complex nature of Alzheimer’s disease (AD) has made it difficult to identify therapeutic targets that are causally involved in the disease process. However, accumulating evidence from experimental and clinical studies that investigate the early disease process point towards the required role of tau in AD etiology. Importantly, a large number of studies investigate and characterize the plethora of pathological forms of tau protein involved in disease onset and propagation. Immunotherapy is one of the most clinical approaches anticipated to make a difference in the field of AD therapeutics. Tau –targeted immunotherapy is the new direction after the failure of amyloid beta (Aß)-targeted immunotherapy and the growing number of studies that highlight the Aß-independent disease process. It is now well established that immunotherapy alone will most likely be insufficient as a monotherapy. Therefore, this review discusses updates on tau-targeted immunotherapy studies, AD-relevant tau species, updates on promising biomarkers and a prospect on combination therapies to surround the disease propagation in an efficient and timely manner., Graphical Abstract

Flow cytometric diagnosis and minimal residual disease (MRD) assessment of precursor B-lineage acute lymphoblastic leukemia (B-ALL) are heavily dependent on CD19 based gating strategies. However, this approach is not optimal in the diagnosis and follow-up of CD19 negative or dim B-ALLs. Though CD19 negative B-ALLs are rare, in the current era of CD19 targeted immuno-therapy, CD19 negative B-ALL relapses are frequent. We have presented our cohort of 14 de novo CD19 negative and dim B-ALLs and have highlighted the difficulties faced during diagnosis and MRD assessment of these patients. We have also discussed the need to identify alternative B-lineage gating markers and strategies to deal with such scenarios.

Background Rheumatic immune-related adverse events (irAEs) are increasingly recognized musculoskeletal manifestations in cancer patients receiving immune checkpoint targeted immunotherapy (1). Since they represent a spectrum of new clinical entities and a robust evidence base is lacking, a task force was convened to harmonize expert consensus regarding their identification and management due to the lack of dedicated clinical trials. Objectives To develop EULAR recommendations for the diagnosis and the management of rheumatic irAEs due to cancer immunotherapy, based on literature and expert opinion. Methods Recommendations were developed according to the 2014 EULAR Standard Operating Procedures. The task force consisted of 19 clinical experts from Europe and North America (14 rheumatologists, 2 internists and 3 oncologists), 1 clinical epidemiologist, 1 allied health professional and 2 patient representatives. During the first meeting, the group defined the focus of the task force, the target population, and formulated research questions. A systematic literature research was performed by one fellow (MK) with the help of a librarian. Based on available evidence and using a consensus procedure, recommendations were developed during a second meeting. The level of agreement was determined by an anonymous voting process. Results 4 overarching principles and 10 recommendations were developed. The overarching principles define the role of rheumatologists and highlight the shared decision-making process between patients, oncologists and rheumatologists. One recommendation addresses the referral process, two address the diagnosis, and five address the therapeutic strategy of cancer patients experiencing rheumatic, musculoskeletal, and systemic signs or symptoms while receiving immunotherapy. An additional recommendation was included to address pre-existing rheumatic conditions and the last focuses on the diagnostic approach before immunotherapy. Conclusion These recommendations provide the basis of a EULAR consensus on the diagnosis and the management of rheumatic irAEs. Reference [1] Calabrese LH, Calabrese C, Cappelli LC. Rheumatic immune-related adverse events from cancer immunotherapy. Nat Rev Rheumatol. 2018 Oct;14(10):569-579. Disclosure of Interests Marie Kostine: None declared, Axel Finckh Grant/research support from: Bristol-Myers Squibb, Pfizer Inc, Consultant for: AbbVie, A2Bio, Bristol-Myers Squibb, MSD, Roche, Pfizer Inc, and UCB, Clifton Bingham Grant/research support from: BMS, Consultant for: AbbVie, BMS, Eli Lilly, Genentech/Roche, Janssen, Pfizer, Sanofi/Regeneron, Karen Visser: None declared, Jan Leipe Grant/research support from: Novartis, Pfizer; Scientific Support: Novartis, Pfizer, Consultant for: AbbVie, AstraZeneca, Bristol-Myers Squibb, Celgene, Hospira, Janssen-Cilag, LEO Pharma, Lilly, Novartis, Roche, Sanofi, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Janssen-Cilag, Lilly, Novartis, MSD, Pfizer, Roche, Sanofi, UCB, Hendrik Schulze-Koops Grant/research support from: Novartis, Pfizer, Roche, Consultant for: Abbvie, Actelion, Amgen, AstraZeneca, Biogen International, BMS, Celgene, Chugai, GSK, Hospira, Janssen-Cilag, Leo Pharmaceuticals, Lilly, MSD, Medac, Merck, Novartis, Pfizer, Hexal Sandoz, Sanofi, Roche, UCB, Paid instructor for: Abbvie, Actelion, Amgen, AstraZeneca, Biogen International, BMS, Celgene, Chugai, GSK, Hospira, Janssen-Cilag, Leo Pharmaceuticals, Lilly, MSD, Medac, Merck, Novartis, Pfizer, Hexal Sandoz, Sanofi, Roche, UCB, Speakers bureau: Abbvie, Actelion, Amgen, AstraZeneca, Biogen International, BMS, Celgene, Chugai, GSK, Hospira, Janssen-Cilag, Leo Pharmaceuticals, Lilly, MSD, Medac, Merck, Novartis, Pfizer, Hexal Sandoz, Sanofi, Roche, UCB, Ernest Choy Grant/research support from: Amgen, Bio-Cancer, Chugai Pharma, Ferring Pharmaceuticals, Novimmune, Pfizer, Roche, and Union Chimique Belge, Consultant for: Abbvie, Amgen, AstraZeneca, Biogen, BMS, Boehringer Ingelheim, Celgene, Chelsea Therapeutics, Chugai Pharma, Daiichi Sankyo, Eli Lilly, Ferring Pharmacuetical, GlaxoSmithKline, Hospita, ISIS, Jazz Pharmaceuticals, Janssen, MedImmune, Merrimack Pharmaceutical, Merck Sharp & Dohme, Napp, Novimmune, Novartis, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, SynAct Pharma, Sanofi-Genzyme, Tonix and Union Chimique Belge, Speakers bureau: Amgen, BMS, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Hospira, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis, and Union Chimique Belge, Karolina Benesova Grant/research support from: Scientific Projects (IIT) I’m involved in as an investigator have been supported, but not initiated or designed by Abbvie and Novartis, Consultant for: Advisory board member on early disease detection for Novartis, Timothy R. Radstake: None declared, Andrew Cope: None declared, Oliver Lambotte: None declared, Jacques-Eric Gottenberg Grant/research support from: Bristol-Myers Squibb, Grant/research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Lilly, Pfizer, Sanofi-Genzyme, UCB Pharma, Consultant for: Bristol-Myers Squibb, Eli Lilly, UCB, Sanofi-Genzyme, Pfizer, Yves Allenbach: None declared, Marianne Visser: None declared, Cindy Rusthoven: None declared, Lone Thomasen: None declared, Shahin Jamal Consultant for: Consultant for Abbvie, Amgen, BMS, Eli Lilly, Pfizer, Janssen, Merck, UCB, Aurelien Marabelle: None declared, James Larkin: None declared, John Haanen Consultant for: Amgen, Merck, MSD, Helsinn, Tesaro and Hexaland, Leonard Calabrese Consultant for: Bristol-Myers-Squibb, Genentech and Astra-Zeneca., Xavier Mariette Grant/research support from: Servier, Consultant for: AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Pfizer, UCB Pharma, Thierry Schaeverbeke: None declared

Significance This paper discusses the successes and failures of tyrosine kinase inhibitors in treating cancer, and why we believe targeted immunotherapy may provide more durable remissions. Tyrosine kinases are central to tumor development and progression. Since we originally demonstrated specific inhibition of tyrosine kinases, with minimal toxicity, a large number of tyrosine kinase inhibitors—both small molecules and antibodies—have entered the clinic. Nonetheless, tumors are heterogeneous and highly mutable, and they eventually bypass tyrosine kinase inhibition. The immune system has the ability to seek and destroy tumor cells. Tumors avoid detection by the immune system, so the goal is to reinstate immune surveillance against the tumor.

Until recently, the treatment of small cell lung cancer (SCLC), a malignancy classically described as having a robust response to first-line therapy with near-universal recurrence, has remained relatively unchanged. Advancements in the management of SCLC have lagged behind those seen for non-small cell lung cancers. As the era of precision medicine and targeted immunotherapy evolves, radiologists must be familiar with the modern treatment paradigms of SCLC and associated imaging patterns, including classic and nonclassic appearances of treatment complications.

e16121 Background: Programmed cell death protein‐1(PD-1) targeted immunotherapy is a promising treatment strategy for advanced hepatocellular carcinoma. Anti-PD-1 inhibitor camrelizumab showed antitumour activity in phase II studies of advanced hepatocellular carcinoma, with manageable toxicities. This study evaluates safety and efficacy of camrelizumab in patients with advanced hepatocellular carcinoma. Methods: This is a multicentre, real‐world trial done at thirty-three centres in Fujian Province, China. Eligible patients were aged 18 to 75 years was diagnosed by China Liver Cancer Staging(CNLC) 2019 clinical diagnostic criteria or with a histological or cytological diagnosis of advanced hepatocellular carcinoma, unresectable or had progressed on or were intolerant to previous systemic treatment, and had an Eastern Cooperative Oncology Group performance score of 0-1. Patients were received camrelizumab 200 mg intravenously every 2 weeks plus other treatments, such as molecular targeted drug, transcatheyer artetial chemoembolization, radiotherapy and chemotherapy. The primary endpoints were progression-free survival. Safety was analysed in all treated patients. Follow-up is ongoing. Results: Between Mar 12, 2020, and Dec 25, 2020, 63 patients were screened for eligibility, of whom 41 eligible patients received camrelizumab were recruited and among whom 15 received apatinib, 16 received lenvatinib, 2 received sorafenib and 1 received regorafenib. Median followup was 5.28 months (IQR 1.63–10.20). Objective response was reported in 12 (29.3%; 95% CI 16.1–45.5) of 41 patients. Disease control was reported in 34 (82.9%; 95% CI 67.9–92.8) of 41 patients. The median PFS was not reached, and expected more than 9 months. Grade 3 or 4 treatment-related adverse events occurred in 21 (51.2%) of 41 patients; the most common were increased gamma-glutamyltransferase (15 [36.6%]) and increased aspartate aminotransferase (7 [17%]). One death was judged by the investigators to be potentially treatment-related (due to upper gastrointestinal bleeding). Conclusions: Camrelizumab showed promising efficacy and safety in pretreated Chinese patients with advanced hepatocellular carcinoma, and might represent a new treatment option for these patients. Clinical trial information: ChiCTR2000041405. Research Sponsor: Jiangsu Hengrui Medicine Co., Ltd. Clinical trial information: ChiCTR2000041405.

The pathogenesis of Tuberculous meningitis (TBM) is poorly understood, but contemporary molecular biology technologies have allowed for recent improvements in our understanding of TBM. For instance, neutrophils appear to play a significant role in the immunopathogenesis of TBM, and either a paucity or an excess of inflammation can be detrimental in TBM. Further, severity of HIV-associated immunosuppression is an important determinant of inflammatory response; patients with the advanced immunosuppression (CD4+ T-cell count of 150 cells/μL. Host genetics may also influence outcomes with LT4AH genotype predicting inflammatory phenotype, steroid responsiveness and survival in Vietnamese adults with TBM. Whist in Indonesia, CSF tryptophan level was a predictor of survival, suggesting tryptophan metabolism may be important in TBM pathogenesis. These varying responses mean that we must consider whether a “one-size-fits-all” approach to anti-bacillary or immunomodulatory treatment in TBM is truly the best way forward. Of course, to allow for proper treatment, early and rapid diagnosis of TBM must occur. Diagnosis has always been a challenge but the field of TB diagnosis is evolving, with sensitivities of at least 70% now possible in less than two hours with GeneXpert MTB/Rif Ultra. In addition, advanced molecular techniques such as CRISPR-MTB and metagenomic next generation sequencing may hold promise for TBM diagnosis. Host-based biomarkers and signatures are being further evaluated in childhood and adult TBM as adjunctive biomarkers as even with improved molecular assays, cases are still missed. A better grasp of host and pathogen behaviour may lead to improved diagnostics, targeted immunotherapy, and possibly biomarker-based, patient-specific treatment regimens.

// Zhiwei Hu 1, 2 , Jie Xu 2, * , Jijun Cheng 2, ** , Elizabeth McMichael 3 , Lianbo Yu 4 , William E. Carson III 1 1 Department of Surgery, Division of Surgical Oncology, The Ohio State University Medical Center and The James Comprehensive Cancer Center, Columbus, OH, USA 2 Yale University School of Medicine Department of Obstetrics, Gynecology and Reproductive Sciences, New Haven, CT, USA 3 Biomedical Sciences Graduate Program, The Ohio State University Medical Center and The James Comprehensive Cancer Center, Columbus, OH, USA 4 Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University Medical Center and The James Comprehensive Cancer Center, Columbus, OH, USA * Present addresses: Institute of Cancer Stem Cell, Dalian Medical University, China ** Present address: Yale University Department of Genetics, New Haven, CT, USA Correspondence to: Zhiwei Hu, email: Zhiwei.Hu@osumc.edu Keywords: cancer stem cells, solid cancer, tissue factor, targeted immunotherapy, targeted photodynamic therapy Received: October 04, 2016 Accepted: November 09, 2016 Published: November 26, 2016 ABSTRACT Targeting cancer stem cell (CSC) represents a promising therapeutic approach as it can potentially fight cancer at its root. The challenge is to identify a surface therapeutic oncotarget on CSC. Tissue factor (TF) is known as a common yet specific surface target for cancer cells and tumor neovasculature in several solid cancers. However, it is unknown if TF is expressed by CSCs. Here we demonstrate that TF is constitutively expressed on CD133 positive (CD133+) or CD24-CD44+ CSCs isolated from human cancer cell lines, tumor xenografts from mice and breast tumor tissues from patients. TF-targeted agents, i.e., a factor VII (fVII)-conjugated photosensitizer (fVII-PS for targeted photodynamic therapy) and fVII-IgG1Fc (Immunoconjugate or ICON for immunotherapy), can eradicate CSC via the induction of apoptosis and necrosis and via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, respectively. In conclusion, these results demonstrate that TF is a novel surface therapeutic oncotarget for CSC, in addition to cancer cell TF and tumor angiogenic vascular endothelial TF. Moreover, this research highlights that TF-targeting therapeutics can effectively eradicate CSCs, without drug resistance, isolated from breast, lung and ovarian cancer with potential to translate into other most commonly diagnosed solid cancer, in which TF is also highly expressed.

Metastatic renal cell carcinoma (mRCC) has seen the introduction of numerous new treatments over the past decade. However, the efficacy of these therapies has plateaued, and new treatment options are needed for the majority of patients with mRCC whose disease inevitably progresses through one or more standard therapies ('refractory' mRCC). Recently approved agents in this space have shown great promise.This article reviews the evidence behind current management strategies for mRCC. After reviewing clinical trials that established current first-line therapies and agents used in the refractory setting, we address new ideas for the treatment of refractory disease including combination therapies and novel targeted agents. In particular, we focus on targeted immunotherapy in refractory mRCC. We conclude by considering future directions in combination treatments utilizing these novel agents.Numerous approaches have produced tangible benefits for the treatment of patients with mRCC. These include development of next generation VEGFR/TKIs, targeted immunotherapy agents, and the development of combined regimens. In particular, immunotherapy agents targeting the PD1/PD-L1 pathway have shown great promise with a robust survival advantage seen in patients treated with nivolumab. A tolerable side effect profile of immunotherapy agents makes them amenable for use in combination therapies and ongoing trials are addressing this question.

The better understanding of interactions between tumor and immune system (e.g., tumor-associated upregulation of PD-L1 to induce checkpoint for cytotoxic lymphocytes; Figure 1A ) gave rise to the development of immune modulating therapies.

The treatment of multiple myeloma (MM) has entered into a new era of immunotherapy. Novel immunotherapies will significantly improve patient outcome via simultaneously targeting malignant plasma cell (PC) and reversing immunocompromised bone marrow (BM) microenvironment. B-cell maturation antigen (BCMA), selectively expressed in PCs and a key receptor for A proliferation-inducing ligand (APRIL), is highly expressed in MM cells from patients at all stages. The APRIL/BCMA signal cascades promote the survival and drug resistance of MM cells and further modulate immunosuppressive BM milieu. Impressively, anti-BCMA immunotherapeutic reagents, including chimeric antigen receptor (CAR), antibody-drug conjugate (ADC) and bispecific T cell engager (BiTE) have all shown high response rates in their first clinical trials in relapse and refractory patients with very limited treatment options. These results rapidly inspired numerous development of next-generation anti-BCMA biotherapeutics, i.e., bispecific molecule, bispecific or trispecific antibodies, a novel form of CAR T/NK cells and T Cell Antigen Coupler (TAC) receptors, antibody-coupled T cell receptor (ACTR) as well as a cancer vaccine. We here highlight seminal preclinical and clinical studies on novel BCMA-based immunotherapies as effective monotherapy and discuss their potential in combination with current anti-MM and novel checkpoint drugs in earlier disease stages to further achieve durable responses in patients.

e16647 Background: Novel oncological treatment strategies for hepatocellular carcinoma (HCC) include immunotherapies targeting programmed death protein 1 (PD-1). To date there is scarce data on the current real-world clinical utilization of immunotherapy for HCC in the US. Methods: The Flatiron Health EHR-derived de-identified database was queried in October 2019 for adult patients with advanced HCC. PD-1 targeted immunotherapy (PD-1 IMT) included Nivolumab and Pembrolizumab. Overall survival (OS) was evaluated using Cox proportional hazards models. Multivariable analyses adjusted for patient demographics (age, gender, race), documented liver disease risk factors (obesity, diabetes, alcohol abuse, hepatitis), documented liver disease complication (ascites, encephalopathy), local HCC treatment (resection, radiofrequency ablation, transarterial chemoembolization [TACE], transarterial radioembolization [TARE]) and systemic Sorafenib. Subgroup analyses were performed in patients with documented clinical performance status (Eastern Cooperative Oncology Group; ECOG) and albumin/bilirubin results (all measured nearest to HCC diagnosis). Results: A total of 2,912 patients with advanced HCC were included, of which n = 345 (11.8%) received PD-1 IMT. Utilization of PD-1 IMT continuously increased from 2004, accounting for 20.9% of all cases in 2018/19. Patients treated with and without PD-1 IMT were comparable regarding demographics, comorbidities and liver disease. PD-1 IMT was more commonly administered at academic centers (20.3% vs. 13% in non-academic centers, p < 0.001), and in patients receiving Sorafenib, TACE, TARE or HCC resection (vs. none of these treatments, each p < 0.05). Median follow-up time was 36.1 months. In univariate analyses, administration of PD-1 IMT was associated with longer OS (vs. no PD-1 IMT; HR = 0.67, 95% CI: 0.58-0.78, p < 0.001; OS rates in the table). In multivariable analyses, PD-1 IMT receipt was an independent prognosticator (vs. no PD-1 IMT; HR = 0.54, 95% CI: 0.46-0.63, p < 0.001). In a subset of n = 1560 patients, this effect persisted after adjustment for ECOG, albumin and bilirubin results (HR = 0.58; 95% CI: 0.48-0.69, p < 0.001). Conclusions: PD-1 targeted immunotherapy is increasingly used for advanced HCC, accounting for up to 20.9% of cases in 2018/19. After adjustment for potential confounders, immunotherapy was associated with an overall survival benefit. [Table: see text]