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Chimeric antigen receptor T cell therapy has been established in the treatment of various B cell malignancies. However, translating this therapeutic effect to treat solid tumors has been challenging because of their inter-tumoral as well as intratumoral heterogeneity and immunosuppressive microenvironment. Local interventions, such as surgery, radiotherapy, local ablation, and locoregional drug delivery, can enhance chimeric antigen receptor T cell therapy in solid tumors by improving tumor infiltration and reducing systemic toxicities. Additionally, ablation and radiotherapy have proven to (re-)activate systemic immune responses via abscopal effects and reprogram the tumor microenvironment on a physical, cellular, and chemical level. This review highlights the potential synergy of the combined approaches to overcome barriers of chimeric antigen receptor T cell therapy and summarizes recent studies that may pave the way for new treatment regimens., (© 2024. The Author(s).)

Background: Immunotherapies such as immune checkpoint inhibitors (ICI) are effective in multiple tumor entities but induce a plethora of side effects. Comprehensive real-world analyses are essential to identify new signals, characterize diagnostic features, enable risk assessment, determine pathomechanisms, assess effectiveness of side effect management and compare tumor outcomes., Methods: The international online `Side-Effect Registry Immuno-Oncology´ (SERIO; www.serio-registry.org) collects rare, complex, and severe immunotherapy-induced side effects across all tumor entities with a strong focus on ICI-induced immune-related adverse events (irAE). The relational database management system (RDMS) contains structured data on patient and tumor characteristics, type of immunotherapy, treatment of side effects, and outcome of tumor and irAE. Data are captured within 25 organ modules including new modules for immune effector cell-associated neurotoxicity syndrome (ICANS) for CAR-T-cell therapies and cytokine release syndrome (CRS) for bispecific antibodies. Information on biological samples is gathered., Results: A total of 1398 irAE cases have been documented by 58 centers from 13 countries in patients with 17 tumor types. IrAEs were induced by nine different immunotherapies including tebentafusp and CAR-T cell therapies, and resulted, among others, in neurological (7.6%), pulmonary (4.0%), and cardiac toxicities (2.9%). 50.0% of all irAEs were graded severe or life-threatening and 23.0% of patients received second-line therapy for steroid-refractory or steroid-dependent irAE. SERIO has contributed to 44 original publications on topics ranging from irMyocarditis to irEncephalitis to long-term persistent sequelae of immunotherapy., Conclusions: A reliable evidence base is crucial for decision-making in rare, complex or therapy-refractory irAE. SERIO can help optimize side effect management and thereby reduce morbidity and mortality induced by immunotherapy., Competing Interests: Declaration of Competing Interest LH received speaker and consultancy fees from BiomeDx, BMS, Kyowa Kirin, Merck, MSD, Myoncare, Novartis, Pierre-Fabre, Roche, Sanofi, SUN and Therakos. The LMU received research grants or clinical study grants from Agenus, AstraZeneca Inc., BMS, Hoffmann-La Roche AG, Huya Bioscience, Immunocore, IO Biotech, Merck, Merck Sharp & Dome GmbH, Miltenyi Biomedicine GmbH, Novartis, Pfizer, Pierre Fabre, Regeneron, Replimune, and Sanofi Aventis. AF received honoraria for presentations and travel support from: BMS, Novartis, Pierre-Fabre. AF reports on participation on Advisory Boards of MSD, BMS, Novartis, Pierre-Fabre, Immunocore and institutional research grants from BMS Stiftung Immunonkologie for other financial or non-financial interests. AH reports grants and personal fees from Amgen, grants and personal fees from BMS, grants and personal fees from MerckPfizer, grants and personal fees from MSD/Merck, grants and personal fees from Philogen, grants and personal fees from Pierre Fabre, grants and personal fees from Regeneron, grants and personal fees from Roche, grants and personal fees from Sanofi-Genzyme, grants and personal fees from Novartis Pharma, grants and personal fees from Eisai, personal fees from Immunocore, grants and personal fees from Replimune, personal fees from Seagen, personal fees from IO Biotech, personal fees from Dermagnostix, personal fees from Incyte, grants and personal fees from NeraCare, personal fees from Highlight Therapeutics, grants from Huya Biosciences, personal fees from Kyowa Kirin, personal fees from Iovance, outside the submitted work. CL received honoraria (lectures, presentations, speakers bureaus, manuscript writing or educational events) and travel support from: BMS, MSD Merck, Pierre-Fabre, Biontech, Almirall Hermal, Sun Pharma, KyowaKirin, Immunocore, Sanofi, Novartis. CP received honoraria (speaker honoraria or honoraria as a consultant) and travel support from: Novartis, BMS, MSD, Merck Serono, MSD, Celgene, AbbVie, Sunpharma, Pierre Fabre, UCB, Nutricia Milupa, Janssen and LEO outside the submitted work. CR reports personal consulting fees from BMS, Roche, MSD, Sanofi, Pierre Fabre, Sunpharma, Pfizer, Regeneron. CR received honoraria (lectures, presentations, speakers bureaus, manuscript writing or educational events) from Pierre Fabre, Sanofi, BMS. CR reports personal fees (participation on a Data Safety Monitoring Board or Advisory Board) from Ultimovacs and Regeneron. CR reports stocks/stock options: Ribonexus. DS reports grants, personal fees, non-financial support and other from Novartis, BMS, Amgen, MSD & Array/Pfizer; personal fees and from 4SC, Agenus, Array BioPharma, Astra Zeneca, BioAlta, CureVac, Daiichi Sanyko, Erasma, Haystack, Immatics, Immunocore, InFlarX, Merck Serono, Pierre Fabre, PamGene, Philogen, Neracare NoviGenix, Ultimovacs, Sandoz/Hexal, Sanofi, Seagen, Sun Pharma, Regeneron, and Replimune. GMcA reports on grants or contracts from BMS, Genentech-Roche, Merck to his institution. DT reports consultancy, speaker fees or travel grants: BMS, Roche, Novartis, Sanofi, Recordati, Kyowa Kirin, Sun Pharma and Pierre Fabre. GMcA reports on participation on Data Safety Monitoring or Advisory Board from Pierre Fabre and Pfizer (no payments) and on National Breast Cancer Foundation Board (Australia) (no payments). GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. HG reports on grants or contracts from BMS, Roche, MSD Oncology, Amgen, Novartis, Iovance Biotherapeutics to her institution. HG received consulting fees from BMS, MSD Oncology, Pierre Fabre, Sanofi/ Regeneron. HG received speakers honoraria from BMS, MSD Oncology, Pierre-Fabre, Sanofi/ Regeneron. HG received travel support from MSD, Amgen, Pfizer. JH received scientific grants from BMS, Sanofi, Sunpharma and consulting fees (for advisory boards) from GSK, MSD, Pierre Fabre, Onkowiessen, Sunpharma. JH received honoraria (talks) from Amgen, BMS, GSK, Immunocore, MSD, Novartis, Pierre Fabre, Sanofi, Sunpharma. JH received meeting/travel support from BMS, Iovance, Sunpharma. JH reports on participation on a Data Safety Monitoring Board from Nekvax. LZ declares speakers and advisory board honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma, research support from Novartis and travel support from Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma and Novartis; outside the submitted work. MS reports on research support from Amgen, BMS/Celgene, Gilead/Kite, Janssen, Miltenyi, Novartis, Roche, Seattle Genetics, Takeda. MS reports on participation on Advisory Boards of Astra Zeneca, Avencell, Ichnos, Incyte, Janssen, Molecular Partners. MS received honoraria (speaker’s bureau) from: Amgen, BMS/Celgene, Janssen, Gilead/Kite, Novartis, Pfizer, Takeda. PA reports on grants and contracts from BMS, Roche-Genentech, Pfizer, Sanofi. PA received consulting fees from Bristol Myers Squibb, Roche-Genentech, Merck, Sharp & Dohme, Novartis, Merck Serono, PierreFabre, Sun Pharma, Sanofi, Sandoz, Italfarmaco, Nektar, Pfizer, Lunaphore, Medicenna. Bio-Al Health, ValoTx, Replimmune, Bayer. PA received travel support from Pfizer, BIO-AI Health, Replimmune. PA reports on participation on a Data Safety Monitoring or Advisory Board from BMS, Roche-Genentech, Merck, Sharp & Dohme, Novartis, AstraZeneca, BoehringerIngelheim, Eisai, Regeneron, Daiichi Sankyo, Oncosec, Nouscom, Seagen, iTeos, Erasca. RD has intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer, Simcere and touchIME outside the submitted work. RG received honoraria for advice and lectures from BristolMyers Squibb, Roche Pharma, MerckSharpDohme, Novartis, Merck-Serono, Amgen, Almirall Hermal, Pierre-Fabre, Sun Pharma, Immunocore, 4SC, Delcath, Sanofi/Regeneron. Ralf Gutzmer received travel support from SUN Pharma, Boehringer Ingelheim and PierreFabre. Ralf Gutzmer received research grants from Novartis, Sanofi/Regeneron, Merck Serono, Amgen, SUN Pharma, KyowaKirin, Admiral Hermal. RK received meeting and travel support from SunPharma, Novartis, Pierre-Fabre. SG reports on clinical trials honoraria to institution from MSD, BMS, Sanofi, Pfizer, BioNTech, EORTC, I-O Biotech, Astra Zeneca, and Regeneron. SG received consulting fees from MSD and BMS and an Online Ticket for ASCO from BMS. TE received speaker and consultancy fees from BMS, Curevac, Merck, MSD, Novartis, Pierre-Fabre, Sanofi, Almiral Hermal, and SUN. TN reports on grants or contracts from NIH, BMS, Astra Zeneca to his institution. TN received consulting fees from Genentech, BMS, Roche, Sanofi, Roivant, Race Oncology. TN participated on Data Safety Monitoring Board/ Advisory Board from Genentech. TR declared speaker’s honoraria and travel grants from Therakos and SUN. AR, CE, MK, VM have declared no conflicts of interest. BR received support from BMS, Merck and Astrazeneca. BR received honoraria (for lectures, presentations, speakers bureaus, manuscript writing or educational events) from BMS, Merck and Astrazeneca. BR reports on participation on a Data Safety Monitoring Board or Advisory Board from BMS, Merck and Astrazeneca. All remaining authors have declared no conflicts of interest., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Chimeric antigen receptor T-cell therapy (CART) can be administered outpatient yet requires management of potential side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The pre-infusion tumor burden is associated with CRS, yet there is no data on the relevance of pre-infusion tumor growth rate (TGR). Our objective was to investigate TGR for the occurrence and severity of CRS and ICANS. Consecutive patients with available pre-baseline and baseline (BL) imaging before CART were included. TGR was determined as both absolute (abs) and percentage change (%) of Lugano criteria-based tumor burden in relation to days between exams. CRS and ICANS were graded according to ASTCT consensus criteria. Clinical metadata was collected including the international prognostic index (IPI), patient age, ECOG performance status, and LDH. Sixty-two patients were included (median age: 62 years, 40% female). The median pre-BL TGR [abs] and pre-BL TGR [%] was 7.5 mm 2 /d and 30.9%/d. Pre-BL TGR [abs] and pre-BL TGR [%] displayed a very weak positive correlation with the grade of CRS (r[abs] = 0.14 and r[%] = 0.13) and no correlation with ICANS (r[abs] =  - 0.06 and r[%] =  - 0.07). There was a weak positive correlation between grade of CRS and grade of ICANS (r = 0.35; p = 0.005) whereas there was no significant correlation of CRS or ICANS to any other of the examined parameters. The pre-infusion TGR before CART was weakly associated with the occurrence of CRS, but not the severity, whereas there were no significant differences in the prediction of ICANS. There was no added information when compared to pre-infusion tumor burden alone. Outpatient planning and toxicity management should not be influenced by the pre-infusion TGR., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The clinical application of chimeric antigen receptor (CAR) T-cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood-borne cancer types. However, CAR T-cell therapy can lead to severe therapy-associated toxicities including CAR-related hematotoxicity, ON-target OFF-tumor toxicity, cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Just as CAR T-cell therapy has evolved regarding receptor design, gene transfer systems and production protocols, the management of side effects has also improved. However, because of measures taken to abrogate adverse events, CAR T-cell viability and persistence might be impaired before complete remission can be achieved. This has fueled efforts for the development of extrinsic and intrinsic strategies for better control of CAR T-cell activity. These approaches can mediate a reversible resting state or irreversible T-cell elimination, depending on the route chosen. Control can be passive or active. By combination of CAR T-cells with T-cell inhibiting compounds, pharmacologic control, mostly independent of the CAR construct design used, can be achieved. Other strategies involve the genetic modification of T-cells or further development of the CAR construct by integration of molecular ON/OFF switches such as suicide genes. Alternatively, CAR T-cell activity can be regulated intracellularly through a self-regulation function or extracellularly through titration of a CAR adaptor or of a priming small molecule. In this work, we review the current strategies and mechanisms to control activity of CAR T-cells reversibly or irreversibly for preventing and for managing therapy-associated toxicities., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background Aims: Chimeric antigen receptor T-cell therapy (CART) prolongs survival for patients with refractory or relapsed lymphoma, yet its efficacy is affected by the tumor burden. The relevance of tumor kinetics before infusion is unknown. We aimed to study the prognostic value of the pre-infusion tumor growth rate (TGR pre-BL ) for progression-free (PFS) and overall survival (OS)., Methods: Consecutive patients with available pre-baseline (pre-BL) and baseline (BL) computed tomography or positron emission tomography/computed tomography scan before CART were included. TGR was determined as change of Lugano criteria-based tumor burden between pre-BL, BL and follow-up examinations (FU) in relation to days between imaging exams. Overall response rate (ORR), depth or response (DoR) and PFS were determined based on Lugano criteria. Multivariate regression analysis studied association of TGR with ORR and DoR. Proportional Cox regression analysis studied association of TGR with PFS and OS., Results: In total, 62 patients met the inclusion criteria. The median TGR pre-BL was 7.5 mm 2 /d (interquartile range -14.6 mm 2 /d to 48.7 mm 2 /d); TGR pre-BL was positive (TGR pre-BL POS ) in 58% of patients and negative (TGR pre-BL NEG , indicating tumor shrinkage) in 42% of patients. Patients who were TGR pre-BL POS had a 90-day (FU2) ORR of 62%, a DoR of -86% and a median PFS of 124 days. Patients who were TGR pre-BL NEG had a 90-day ORR of 44%, DoR of -47% and a median PFS of 105 days. ORR and DoR were not associated with slower TGR (P = 0.751, P = 0.198). Patients with an increase of TGR from pre-BL over BL to 30-day FU (FU1) ≥100% (TGR pre-BL-to-FU1≥100% ) showed a significant association with shorter median PFS (31 days versus 343 days, P = 0.002) and shorter median OS after CART (93 days versus not reached, P < 0.001), compared with patients with TGR pre-BL-to-FU1<100% ., Conclusions: In the context of CART, differences in pre-infusion tumor kinetics showed minor differences in ORR, DoR, PFS and OS, whereas the change of the TGR from pre-BL to 30-day FU significantly stratified PFS and OS. In this patient population of refractory or relapsed lymphomas, TGR is readily available based on pre-BL imaging, and its change throughout CART should be explored as a potential novel imaging biomarker of early response., Competing Interests: Declaration of Interest Statement VB: BMS/Celgene: research funding; Kite/Gilead: consultancy, honoraria, research funding; Janssen: research funding, honoraria; Novartis: research funding, honoraria; Roche: research funding; Takeda: research funding. KR: Kite/Gilead: research funding; Kite/Gilead: travel support; Novartis: honoraria. VLB: Amgen: honoraria; Celgene/BMS: research funding; Kite/Gilead: research funding, honoraria; Novartis: honoraria; Pfizer: honoraria. CS: Kite/Gilead: travel support. MvB: Astellas: consultancy, research funding and honoraria; BMS: consultancy, research funding and honoraria; Kite/Gilead: consultancy, research funding and honoraria; Miltenyi: consultancy, research funding and honoraria; Mologen: consultancy, research funding and honoraria; MSD Sharp & Dohme: consultancy, research funding and honoraria; Novartis: consultancy, research funding and honoraria; Roche: consultancy, research funding and honoraria. M.S.: Amgen: research funding, speakers bureau; Astra Zeneca: speakers bureau; Aven Cell: consultancy, BMS/Celgene: research funding, speakers bureau; CDR-Life: consultancy, Gilead: research funding, speakers bureau; GSK: speakers bureau; Ichnos Sciences: consultancy; Incyte Biosciences: consultancy; Janssen: research funding, consultancy, speakers bureau; Miltenyi Biotec: research funding, consultancy; Morphosys: research funding; Molecular Partners: consultancy; Novartis: research funding, consultancy, speakers bureau; Pfizer: consultancy, speakers bureau; Roche: research funding, speakers bureau; Seattle Genetics: research funding; Takeda: research funding, consultancy, speakers bureau. WGK: Bristol Myers Squibb: advisor. The remaining authors declare no competing financial interests. None of the mentioned conflicts of interest were related to financing of the content of this manuscript., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Monitoring for liver injury remains an important aspect of drug safety assessment, including for oncotherapeutics. When present, drug-induced liver injury may limit the use or result in the discontinuation of these agents. Drug-induced liver injury can exhibit with a wide spectrum of clinical and biochemical manifestations, ranging from transient asymptomatic elevations in aminotransferases (TAEAT) to acute liver failure. Numerous oncotherapeutics have been associated with TAEAT, with published reports indicating a phenomenon in which patients may be asymptomatic without overt liver injury despite the presence of grade ≥3 aminotransferase elevations. In this review, we discuss the occurrence of TAEAT in the context of oncology clinical trials and clinical practice, as well as the clinical relevance of this phenomenon as an adverse event in response to oncotherapeutics and the related cellular and molecular mechanisms that may underlie its occurrence. We also identify several gaps in knowledge relevant to the diagnosis and the management of TAEAT in patients receiving oncotherapeutics, and identify areas warranting further study to enable the future development of consensus guidelines to support clinical decision-making., Competing Interests: J.H.L. has no known competing financial interests or personal relationships, that could have appeared to influence the work reported in this paper. S.K.K. and C.D.B. are employed by and own stock in Amgen Inc. A.H.W. has served on advisory boards for Novartis, Janssen, Amgen, Roche, Pfizer, AbbVie, Servier, Celgene-BMS, Macrogenics, Agios, and Gilead; received research funding to his institution from Novartis, AbbVie, Servier, Celgene-BMS, Astra Zeneca, and Amgen; served on the speakers’ bureau for AbbVie, Novartis, and Celgene. M.S. served in a consulting or advisory role for Amgen, Celgene, Gilead Sciences, Janssen, Novartis, Pfizer, and Seattle Genetics; served on the speakers’ bureau for Amgen, Celgene, Gilead Sciences, Janssen, Novartis, and Pfizer; received travel, accommodations, and expenses from Amgen, Celgene, and Gilead Sciences; received research funding from Amgen, Celgene, Gilead Sciences, Miltenyi Biotec, MorphoSys, Novartis, and Seattle Genetics. The other authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

CD19 CAR T cells induce - in part long-lasting - remissions in heavily pretreated patients with relapsed/refractory B-cell malignancies. However, they are associated with unique toxicities, and patient management therefore requires specific expertise.In this review, we outline the basics of their mode of action and present the currently available data on their efficacy in various B-cell and plasma cell malignancies. Currently approved therapies (Tisagenlecleucel, Axicabtagene ciloleucel, Brexucabtagene autoleucel) for patients are outlined as well as indications where approvals are expected in the near future. We discuss practical aspects of CAR T cell therapy from the patient's initial presentation, over leukapheresis, to CAR T cell transfusion. Additionally, we highlight the pathophysiology and principles of the management of the most common toxicities (cytokine release syndrome [CRS], immune cell associated neurotoxicity syndrome [ICANS] and cytopenias)., Competing Interests: Die Autoren erklären, Forschungsunterstützung von Gilead, Miltenyi Biotec, Morphosys, Roche und Seattle Genetics erhalten zu haben. Darüber hinaus waren sie in Beratungsgremien für BMS, Celgene, Gilead, Pfizer, Novartis und Roche tätig und haben Educational Grants von Novartis, Celgene und Kite Gilead erhalten., (Thieme. All rights reserved.)

CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (T reg ) cells suppress the immune response via inhibitory factors such as transforming growth factor-β (TGF-β). T reg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8 + T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Recent immunotherapeutic approaches have evolved as powerful treatment options with high anti-tumour responses involving the patient's own immune system. Passive immunotherapy applies agents that enhance existing anti-tumour responses, such as antibodies against immune checkpoints. Active immunotherapy uses agents that direct the immune system to attack tumour cells by targeting tumour antigens. Active cellular-based therapies are on the rise, most notably chimeric antigen receptor T cell therapy, which redirects patient-derived T cells against tumour antigens. Approved treatments are available for a variety of solid malignancies including melanoma, lung cancer and haematologic diseases. These novel immune-related therapeutic approaches can be accompanied by new patterns of response and progression and immune-related side-effects that challenge established imaging-based response assessment criteria, such as Response Evaluation Criteria in Solid tumours (RECIST) 1.1. Hence, new criteria have been developed. Beyond morphological information of computed tomography (CT) and magnetic resonance imaging, positron emission tomography (PET) emerges as a comprehensive imaging modality by assessing (patho-)physiological processes such as glucose metabolism, which enables more comprehensive response assessment in oncological patients. We review the current concepts of response assessment to immunotherapy with particular emphasis on hybrid imaging with 18 F-FDG-PET/CT and aims at describing future trends of immunotherapy and additional aspects of molecular imaging within the field of immunotherapy.

The remarkable success of chimeric antigen receptor (CAR)-engineered T cells in pre-B cell acute lymphoblastic leukemia (ALL) and B cell lymphoma led to the approval of anti-CD19 CAR T cells as the first ever CAR T cell therapy in 2017. However, with the number of CAR T cell-treated patients increasing, observations of tumor escape and resistance to CAR T cell therapy with disease relapse are demonstrating the current limitations of this therapeutic modality. Mechanisms hampering CAR T cell efficiency include limited T cell persistence, caused for example by T cell exhaustion and activation-induced cell death (AICD), as well as therapy-related toxicity. Furthermore, the physical properties, antigen heterogeneity and immunosuppressive capacities of solid tumors have prevented the success of CAR T cells in these entities. Herein we review current obstacles of CAR T cell therapy and propose strategies in order to overcome these hurdles and expand CAR T cell therapy to a broader range of cancer patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

CAR-T cells, genetically modified tumor-targeted t-cells, revolutionized the treatment of refractory B-cell malignancies. CAR-T cell treatment however, is invariably associated with severe immune-mediated toxicities, namely Cytokine Release Syndrome (CRS) and neurological toxicity (CRES/ICANS). Although knowledge on the pathomechanism of these toxicities is still very limited, recent findings including mouse models might allow prediction, earlier recognition and targeted treatment of patients suffering from these potentially life-threatening side effects. This article summarizes current knowledge and recent findings on the management of severe CAR-T associated toxicities and gaps of knowledge stressing the importance of an interdisciplinary approach including hematology-oncology and Intensive Care Medicine., Competing Interests: BB war Mitglied in Beratungsgremien von Gilead und erhielt Reisekostenunterstützungen, Forschungsunterstützungen und Beratungshonorare von Gilead, Miltenly und Novartis., (© Georg Thieme Verlag KG Stuttgart · New York.)

Immunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with a broad variety of hematological and solid malignancies. The two main drivers behind this success are checkpoint inhibitors (CPIs) and chimeric antigen receptor (CAR) T cells. This review summarizes seminal findings from clinical and translational studies recently presented or published at important meetings or in top-tier journals, respectively. For checkpoint blockade, current studies focus on combinational approaches, perioperative use, new tumor entities, response prediction, toxicity management and use in special patient populations. Regarding cellular immunotherapy, recent studies confirmed safety and efficacy of CAR T cells in larger cohorts of patients with acute lymphoblastic leukemia or diffuse large B cell lymphoma. Different strategies to translate the striking success of CAR T cells in B cell malignancies to other hematological and solid cancer types are currently under clinical investigation. Regarding the regional distribution of registered clinical immunotherapy trials a shift from PD-1 / PD-L1 trials (mainly performed in the US and Europe) to CAR T cell trials (majority of trials performed in the US and China) can be noted.

Immuno-oncology has undoubtedly started a new era in the treatment of malignant diseases. Within a short time immunotherapeutic therapy concepts have become part of the standard therapy for many tumors. Already, immunotherapy is one of the most potent therapeutic options for the treatment of many malignancies. Despite its impressive achievements, there is still a significant need for improvement and many aspects of the practical application of immunotherapeutic modalities of therapy are unclear. If it succeeds in solving the challenges discussed here, immuno-oncology will certainly be one of the most important pillars of successful tumor therapy in the future. Immunotherapeutic combination therapies offer the opportunity to improve treatment outcomes. The immunological side effects of immunotherapy may sometimes be life-threatening, but if adequately treated they may be associated with a good prognosis. The development of predictive biomarkers is indispensable for effective immunotherapy. The costs of immuno-oncological therapies are sometimes very high. Therefore reasonable solutions must be found., Competing Interests: Vornhagen hat keine wirtschaftlichen oder persönlichen Interessenkonflikte.M. Subklewe hat folgende Interessenkonflikte: Forschungsgelder: Amgen, Roche, Gilead, Oxford Biotherapeutics; Advisory Boards: Amgen, Gilead, Seattle Genetics, Pfizer, Celgene.M. von Bergwelt-Baildon hat folgende Interessenkonflikte: Roche, Astellas, MSD, Miltenyi, Gilead, Astra Zeneca., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: A number of new drugs for tumor immunotherapy have been approved in the past few years. They work by activating T cells to combat tumors., Methods: This review is based on publications on recently approved T-cell-activating drugs that were retrieved by a selective search in PubMed., Results: Randomized, controlled trials of "checkpoint" inhibitors, i.e., inhibitory antibodies for use against tumors, have shown that the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab can prolong the survival of patients with advanced melanoma by 2 to 4 months. No data on median overall survival are yet available for the two programmed-death-1 (PD-1) inhibitors pembrolizumab und nivolumab; the endpoint "tumor response" was achieved in 24% and 32% of patients receiving these drugs, respectively. Grade 3 or 4 adverse effects occurred in 50% of patients receiving ipilimumab and in 12 to 13% of those taking either of the two PD-1-inhibitors. Nivolumab prolonged the median survival of patients with metastatic non-small-cell lung cancer from 6 to 9 months. In refractory or recurrent Philadelphia-chromosome-negative pre-B acute lymphoblastic leukemia (pre-B-ALL), treatment with the bispecific antibody construct blinatumomab led to complete remission in 43% of the patients, while grade 3, 4 or 5 toxicities occurred in 83%., Conclusion: T-cell-directed strategies have been established as a new pillar of treatment in medical oncology. As these drugs have frequent and severe adverse effects, therapeutic decision-making will have to take account not only of the predicted prolongation of survival, but also of the potential for an impaired quality of life while the patient is under treatment.