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Acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) are hematological malignancies with high incidence rates that respond relatively well to conventional therapies. However, a major issue is the clinical emergence of patients with relapsed or refractory (r/r) NHL or ALL. In such circumstances, opportunities for complete remission significantly decline and mortality rates increase. The recent FDA approval of multiple cell-based therapies, Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), Tecartus (Brexucabtagene autoleucel KTE-X19), and Breyanzi (Lisocabtagene Maraleucel), has provided hope for those with r/r NHL and ALL. These new cell-based immunotherapies use genetically engineered chimeric antigen receptor (CAR) T-cells, whose success can be attributed to CAR's high specificity in recognizing B-cell-specific CD19 surface markers present on various B-cell malignancies and the subsequent initiation of anti-tumor activity. The efficacy of these treatments has led to promising results in many clinical trials, but relapses and adverse reactions such as cytokine release syndrome (CRS) and neurotoxicity (NT) remain pervasive, leaving areas for improvement in current and subsequent trials. In this review, we highlight the current information on traditional treatments of NHL and ALL, the design and manufacturing of various generations of CAR T-cells, the FDA approval of Kymriah, Yescarta Tecartus, and Breyanzi, and a summary of prominent clinical trials and the notable disadvantages of treatments. We further discuss approaches to potentially enhance CAR T-cell therapy for these malignancies, such as the inclusion of a suicide gene and use of FDA-approved drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: This is a comprehensive overview of the approved chimeric antigen receptor T-cell products (CAR T-cells), their specific indications, treatment-related side effects, and scientific challenges. CAR T-cells have been introduced to modern hematology over the last years and have changed treatment outcomes in heavily pretreated patients with B-cell and plasma cell malignancies. To date, six commercially available CAR T-cell products have been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA). These advanced therapeutic medicinal products induce strong treatment effects but can also cause adverse events that can potentially be life-threatening. Therefore, a thorough understanding of CAR T-cell function and characteristics is essential for safety and efficacy. This review provides a comprehensive overview of the clinical applications of CAR T-cells, focusing on the approved products and emphasizing their benefits but also indicating limitations and challenges. Chimeric antigen receptor (CAR) T-cell therapy has become a powerful treatment option in B-cell and plasma cell malignancies, and many patients have benefited from its use. To date, six CAR T-cell products have been approved by the FDA and EMA, and many more are being developed and investigated in clinical trials. The whole field of adoptive cell transfer has experienced an unbelievable development process, and we are now at the edge of a new era of immune therapies that will have its impact beyond hematologic malignancies. Areas of interest are, e.g., solid oncology, autoimmune diseases, infectious diseases, and others. Although much has been achieved so far, there is still a huge effort needed to overcome significant challenges and difficulties. We are witnessing a rapid expansion of knowledge, induced by new biomedical technologies and CAR designs. The era of CAR T-cell therapy has just begun, and new products will widen the therapeutic landscape in the future. This review provides a comprehensive overview of the clinical applications of CAR T-cells, focusing on the approved products and emphasizing their benefits but also indicating limitations and challenges. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor T-cell (CAR-T) therapy is increasingly used in patients with refractory haematological malignancies but can induce severe adverse events. We aimed to describe the clinical features and outcomes of patients admitted to the intensive care unit (ICU) after CAR-T therapy. Methods: This retrospective observational cohort study included consecutive adults admitted to either of two French ICUs in 2018–2022 within 3 months after CAR-T therapy. Results: Among 238 patients given CAR-T therapy, 84 (35.3%) required ICU admission and were included in the study, a median of 5 [0–7] days after CAR-T infusion. Median SOFA and SAPSII scores were 3 [2–6] and 39 [30–48], respectively. Criteria for cytokine release syndrome were met in 80/84 (95.2%) patients, including 18/80 (22.5%) with grade 3–4 toxicity. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 46/84 (54.8%) patients, including 29/46 (63%) with grade 3–4 toxicity. Haemophagocytic lymphohistiocytosis was diagnosed in 15/84 (17.9%) patients. Tocilizumab was used in 73/84 (86.9%) patients, with a median of 2 [1–4] doses. Steroids were given to 55/84 (65.5%) patients, including 21/55 (38.2%) given high-dose pulse therapy. Overall, 23/84 (27.4%) patients had bacterial infections, 3/84 (3.6%) had fungal infections (1 invasive pulmonary aspergillosis and 2 Mucorales), and 2 (2.4%) had cytomegalovirus infection. Vasopressors were required in 23/84 (27.4%), invasive mechanical ventilation in 12/84 (14.3%), and dialysis in 4/84 (4.8%) patients. Four patients died in the ICU (including 2 after ICU readmission, i.e., overall mortality was 4.8% of patients). One year after CAR-T therapy, 41/84 (48.9%) patients were alive and in complete remission, 14/84 (16.7%) were alive and in relapse, and 29/84 (34.5%) had died. These outcomes were similar to those of patients never admitted to the ICU. Conclusion: ICU admission is common after CAR-T therapy and is usually performed to manage specific toxicities. Our experience is encouraging, with low ICU mortality despite a high rate of grade 3–4 toxicities, and half of patients being alive and in complete remission at one year. [ABSTRACT FROM AUTHOR]

Background: Cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndrome (ICANS) are well-documented toxicities of CAR T-cell therapy. To mitigate excessive toxicity, our center has formulated treatment protocols (early vs. standard) for timely management of CRS and ICANS with tocilizumab and/or corticosteroids. Methods: This retrospective, single-center analysis included patients treated with CAR T-cell therapy. The goal was to describe the association of two management protocols with toxicity and efficacy outcomes. Results: Fifty-five percent of the 40 patients assigned to early management, out of which 5% and 9% developed grade 3+ CRS and ICANS, respectively. Seventy-seven percent and 41% of these patients received tocilizumab and corticosteroids, respectively. Forty-five percent of patients were stratified as standard management, out of which 0% and 11% developed grade 3+ CRS and ICANS, respectively. Seventeen percent and 28% of these patients received tocilizumab and corticosteroids, respectively. The day +90 overall response rate (ORR) for all patients was 63%, with an ORR of 89% for those managed per early management versus 50% for those managed per standard protocol. Conclusion: Early use of tocilizumab and corticosteroids is effective in preventing excessive CAR-T-related toxicities with no negative impact on efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: It is well recognized now that the development of drug resistance is one of the leading causes of treatment failure in conventional therapies. In comparison, recent improvements in immunotherapy showed promising results in eradicating cancer. Chimeric antigen receptor (CAR)-T-cell therapy is one of the cancer immunotherapies that uses patient's T cells and genetically modifies them to target cancer cells. Although CAR-T-cell therapy has shown remarkable success in treating blood cancer, it has proven far more limited in the treatment of solid tumors in different organs. This review article discussed the chronological development of CAR-T-cell therapies and their treatment options in different types of cancers. This article also addresses the current clinical challenges in CAR-T-cell therapy and recent advancements in developing novel therapeutic strategies with fewer side effects. In recent years, chimeric antigen receptor (CAR)-T-cell therapy has emerged as the most promising immunotherapy for cancer that typically uses patients' T cells and genetically engineered them to target cancer cells. Although recent improvements in CAR-T-cell therapy have shown remarkable success for treating hematological malignancies, the heterogeneity in tumor antigens and the immunosuppressive nature of the tumor microenvironment (TME) limits its efficacy in solid tumors. Despite the enormous efforts that have been made to make CAR-T-cell therapy more effective and have minimal side effects for treating hematological malignancies, more research needs to be conducted regarding its use in the clinic for treating various other types of cancer. The main concern for CAR-T-cell therapy is severe toxicities due to the cytokine release syndrome, whereas the other challenges are associated with complexity and immune-suppressing TME, tumor antigen heterogeneity, the difficulty of cell trafficking, CAR-T-cell exhaustion, and reduced cytotoxicity in the tumor site. This review discussed the latest discoveries in CAR-T-cell therapy strategies and combination therapies, as well as their effectiveness in different cancers. It also encompasses ongoing clinical trials; current challenges regarding the therapeutic use of CAR-T-cell therapy, especially for solid tumors; and evolving treatment strategies to improve the therapeutic application of CAR-T-cell therapy. [ABSTRACT FROM AUTHOR]

Efforts to treat cancer using chimeric antigen receptor (CAR)-T therapy have made astonishing progress and clinical trials against hematopoietic malignancies have demonstrated their use. However, there are still disadvantages which need to be addressed: high costs, and side effects such as Graft-versus-Host Disease (GvHD) and Cytokine Release Syndrome (CRS). Therefore, recent efforts have been made to harness the properties of certain immune cells to treat cancer—not just T cells, but also natural killer (NK) cells, macrophages (Mφ), dendritic cells (DC), etc. In this paper, we will introduce immune cell-based cellular therapies that use various immune cells and describe their characteristics and their clinical situation. The development of immune cell-based cancer therapy fully utilizing the unique advantages of each and every immune cell is expected to enhance the survival of tumor patients owing to their high efficiency and fewer side effects. [ABSTRACT FROM AUTHOR]

Simple Summary: Our real-world experience confirmed that commercial CART therapy can be administered with minimal toxicity. The early referral of patients with low tumor burdens is important as CAR T indications continue to expand. Furthermore, close monitoring and the early recognition of side effects are beneficial to preventing major toxicities and may potentially expand the use of CAR T therapy. Commercially available anti-CD19 chimeric antigen receptor T cells (CARΤ cells) have offered long-term survival to a constantly expanding patient population. Given that novel toxicities including cytokine release syndrome (CRS) and neurotoxicity (ICANS) have been observed, we aimed to document the safety and toxicity of this treatment in a real-world study. We enrolled 31 adult patients referred to our center for CAR T therapy. Tisagenlecleucel was infused in 12 patients, axicabtagene ciloleucel in 14, and brexucabtagene autoleucel in 5. Cytokine release syndrome was noted in 26 patients while neurotoxicity was observed in 7. Tocilizumab was administered for CRS in 18 patients, along with short-term, low-dose steroid administration in one patient who developed grade III CRS and, subsequently, grade I ICANS. High-dose steroids, along with anakinra and siltuximab, were administered in only two MCL patients. With a median follow-up time of 13.4 months, nine patients were then in CR. The progression-free (PFS) and overall survival (OS) rates were 41.2% and 88.1% at one year, respectively. MCL diagnosis, which coincides with the administration of brexucabtagene autoleucel, was the only factor to be independently associated with poor OS (p < 0.001); meanwhile, increased LDH independently predicted PFS (p = 0.027).In addition, CRP at day 14 was associated with a poor OS (p = 0.001). Therefore, our real-world experience confirmed that commercial CAR T therapy can be administered with minimal toxicity. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) outbreaks that resulted in a catastrophic threat to global health, with more than 500 million cases detected and 5.5 million deaths worldwide. Patients with a COVID-19 infection presented with clinical manifestations ranging from asymptomatic to severe symptoms, resulting in acute lung injury, acute respiratory distress syndrome, and even death. Immune dysregulation through delayed innate immune response or impairment of the adaptive immune response is the key contributor to the pathophysiology of COVID-19 and SARS-CoV-2-induced cytokine storm. Symptomatic and supportive therapy is the fundamental strategy in treating COVID-19 infection, including antivirals, steroid-based therapies, and cell-based immunotherapies. Various studies reported substantial effects of immune-based therapies for patients with COVID-19 to modulate the over-activated immune system while simultaneously refining the body's ability to destroy the virus. However, challenges may arise from the complexity of the disease through the genetic variance of the virus itself and patient heterogeneity, causing increased transmissibility and heightened immune system evasion that rapidly change the intervention and prevention measures for SARS-CoV-2. Cell-based therapy, utilizing stem cells, dendritic cells, natural killer cells, and T cells, among others, are being extensively explored as other potential immunological approaches for preventing and treating SARS-CoV-2-affected patients the similar process was effectively proven in SARS-CoV-1 and MERS-CoV infections. This review provides detailed insights into the innate and adaptive immune response-mediated cell-based immunotherapies in COVID-19 patients. The immune response linking towards engineered autologous or allogenic immune cells for either treatment or preventive therapies is subsequently highlighted in an individual study or in combination with several existing treatments. Up-to-date data on completed and ongoing clinical trials of cell-based agents for preventing or treating COVID-19 are also outlined to provide a guide that can help in treatment decisions and future trials. [ABSTRACT FROM AUTHOR]

Purpose: A barrier to widespread adoption of chimeric antigen receptor (CAR) T-cell therapy is toxicity. To address this, we recently developed a novel antibody-T-cell receptor (AbTCR) platform (trademarked as ARTEMIS®) which was designed to leverage natural immune receptor signaling and regulation. The AbTCR platform includes a gamma/delta (γδ) TCR-based AbTCR construct and a separate co-stimulatory molecule, both engineered to be tumor-specific. Here, we aim to assess the safety and preliminary efficacy of a CD19-directed AbTCR T-cell therapy. Methods: We generated ET019003 T cells, which are autologous CD19-directed AbTCR T cells. We then conducted an early phase I study to evaluate the safety and preliminary efficacy of ET019003 T cells for the treatment of CD19-positive relapsed/refractory (r/r) B-cell lymphoma. Results: Sixteen patients enrolled in this study and 12 patients were treated. Of the 12 patients treated, 6 patients (50%) achieved a complete response (CR), and 4 (33%) achieved a partial response (PR) (best objective response rate [ORR] of 83%). CRs were durable, including 2 patients with ongoing CRs for 22.7 months and 23.2 months. ET019003 was well-tolerated with an attractive safety profile. No patients experienced severe (grade ≥ 3) cytokine release syndrome (CRS) and only 1 patient experienced immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade. Significant elevations of cytokine levels were not seen, even in patients with marked expansion of ET019003 T cells. Conclusion: This study provides initial clinical validation of the AbTCR platform as a novel cancer treatment with the potential to provide durable clinical benefit with low toxicity. Trial registration: NCT03642496; Date of registration: August 22, 2018. [ABSTRACT FROM AUTHOR]

Introduction: Regulatory activities aim to facilitate the safe use of novel therapeutics such as genetically engineered chimeric antigen receptor (CAR)-T cells. Toxicities associated with CAR-T-cell therapies have led to modified safety management guidance in clinical trials and the implementation of post-marketing requirements. The aim of this study was to estimate the effect of individual risk-minimizing measures to evaluate the appropriateness of regulatory activities. Methods: We re-examined clinical trial data prior to and after the introduction of revised treatment guidelines; we analysed spontaneous adverse drug reaction (ADR) reports submitted to the EudraVigilance database in 2019/2020 regarding their completeness; and we performed a survey of treatment centres in Germany that have been qualified for the use of commercial CAR-T cells. Results: Lower combined incidences of severe cytokine release syndrome (CRS) as well as neurotoxicity occurred following CAR-T-cell treatment after a revision of management guidelines, suggesting earlier intervention compared to before (12.6% vs. 20.5%). Numerous post-marketing ADR reports lacked information important for case assessment. Full details on treatment indication, CRS onset, outcome, and grading were available for just 38.3% of CRS cases. Survey responses support the majority of regulatory requirements for centre qualification. Time investment was highest for training of healthcare professionals, which required an average of 6.5 staff members (range 2–20) and lasted more than 2 days per person in half of the facilities. The need to harmonize the regulatory requirements for the different CAR-T-cell therapeutics was emphasized. Conclusion: Defined regulatory measures can support the safe and effective use of new therapies and are indicated for structured recording of post-marketing data, and the evaluation of such measures appears to be necessary for the continuous improvement. [ABSTRACT FROM AUTHOR]

Using our lab's feeder-free and chemically defined differentiation protocol, we can robustly generate mature conventional T cells from human induced pluripotent stem cells (hiPSCs). Through CRISPR/Cas gene editing, we integrated a functional iTCR clone, derived from primary human iNKT cells, into the TCR alpha constant (TRAC) locus of hiPSCs. Differentiation of the TRAC engineered hiPSCs using our system yielded mature T cells expressing our iTCR clone. Ongoing studies are investigating strategies to improve selection and expansion of this mature population by providing specific niches during selection and maturation. Further comparison with other TRAC engineered hiPSC-derived T cells by phenotypic and functional assays will help us to elucidate how iTCR expression regulates iNKT cell development, including the acquisition of innate NK cell receptors and cytokine responses post-stimulation. By understanding the ontogeny and downstream signaling of the iTCR in T cells during development, including positive selection and expansion capacity, we can harness specific properties of unconventional T cells to develop more effective off-the-shelf T cell therapeutics for various diseases. Epidermal growth factor receptor (EGFR) is a promising target for treating various solid cancers, including colorectal (CRC), lung, pancreatic, and breast cancer. However, the development of EGFR-specific T-cell products still faces several challenges, such as laborious cell culture procedures, concerns regarding lentivirus-based gene transfection, or insufficient purity of EGFR-specific T cells. Our aim is to develop a novel bi-specific antibody armed-T technology platform that simplifies the manufacturing process to produce highly pure cancer-specific T cell products with the benefits of time-saving, safety, and high anti-cancer efficacy. In this study, we have sucessfully demonstrated that EGFR Armed-T cells, which arm patient's PBMCs with our unique anti-EGFR/anti-CD3 bispecific antibody (BsAb), displayed highly efficient tumor-killing ability in various EGFR-positive cancer cell lines, including colorectal cancer (HT-29, HCT116, COLO, LS174T), lung cancer (A549, CL1-5, HCC827), pancreatic cancer (MiaPaCa, Panc1), and triple-negative breast cancer (MDA-MB-231, MDA-MB-468) in vitro. We found that EGFR Armed-T cells, but not normal T cells, can largely accumulate at EGFR-positive tumors and significantly inhibit tumor growth in SCID mice bearing with human colorectal, breast, or pancreatic tumors, respectively. Furthermore, EGFR Armed-T cells did not cause significant cytokine release syndrome or serum/tissue toxicity in these SCID mice. To initiate a first-in-human (FIH) clinical trial, we successfully manufactured the EGFR Armed-T cell products under GMP conditions. We further proved that these BsAb-armed T cells, but not the naïve T cells, can effectively eliminate human colorectal cancer cells. In conclusion, through the success of our CMC qualification, we are approaching the FIH trial, which was designed for colorectal cancer patients with EGFR downstream mutations (KRAS, NRAS or BRAF). [ABSTRACT FROM AUTHOR]

Introduction: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common toxicities associated with chimeric antigen receptor (CAR) T-cell therapy. Severe grade 3 or higher ICANS is less common and requires the use of corticosteroids with or without an Interleukin (IL)-6 receptor antagonist. Although corticosteroids are effective in the management of CRS and ICANS, their impact on CAR T efficacy remains unknown. Case report: We present the case of a 65-year-old male who received CAR T-cell therapy with brexucabtagene autoleucel for stage I/II Mantle Cell Lymphoma (MCL) and achieved complete remission despite receiving a prolonged course of corticosteroids for severe ICANS. Management and outcome: The patient received treatment with high-dose corticosteroids, tocilizumab, and anakinra, in addition to multiple antiepileptic agents. Despite a remitting relapsing pattern of ICANS, the patient not only recovered from the life-threatening complication but also achieved a complete remission at three months post CAR T. Conclusion: This case describes the successful use of corticosteroids for the management of ICANS in a patient treated with CAR T-cell therapy for MCL. [ABSTRACT FROM AUTHOR]

In recent years, the treatment landscape of multiple myeloma has continued to evolve with the introduction of novel immunotherapies. This progress has translated to improved overall survival for patients, but an unmet need remains in the heavily pretreated and high-risk subsets of patients. Emerging immunotherapies in the form of CAR-T cell therapies have been approved for multiple myeloma. However, CAR-T cell therapy has logistical limitations and there is a need for immunotherapies that are readily available, safe, and effective in RRMM. Currently, pending approval, there are many "off the shelf" bispecific antibodies being developed that target BCMA, GPRC5D, FcRH5 and other cell surface proteins. Preliminary efficacy data has suggested that these bispecific antibody therapies have similar response rates (∼50–80%) in heavily pretreated patients. Similarly, to CAR-T cell therapy, cytokine release syndrome and immune effector cell associated neurotoxicity syndrome are adverse events of key interest and incidence range from ∼40 to 90% and 3 to 20%, respectively. In this review, we highlight the various bispecific immunotherapies under development in the treatment of multiple myeloma with a focus on the data from clinical phase I and II studies. [ABSTRACT FROM AUTHOR]

• RT as a bridging strategy can reduce severe CRS and improve PFS of patients. • RT as a bridging strategy can improve PFS and OS in patients with bulky disease. • Conducting RT as a bridging regimen was an independent factor predicted better PFS. We aimed to analyze the safety and efficacy of a radiation bridging regimen with or without chemotherapy compared with chemotherapy alone prior to CAR T-cell treatment for relapsed/refractory aggressive B-cell lymphoma (r/r ABL). In this study, 45 out of 105 patients enrolled in CD19/22 CAR T-cell "cocktail" clinical trial were excluded, including 34 patients without bridging treatment. Total 60 patients receiving CAR T-cell therapies with bridging regimens as chemotherapy alone (C-CAR-T group, n = 31), and radiotherapy with or without chemotherapy (R-CAR-T group, n = 29) between February 2017 and October 2020 were retrospectively analyzed. No significant toxicities were identified in the R-CAR-T group, and no patients in either group experienced CAR-T-related deaths. However, the R-CAR-T group showed a lower incidence of cytokine release syndrome (CRS) of grade ≥ 3 relative to the C-CAR-T group (0% vs 19.4%, P = 0.036). The incidence of neurological toxicity was 9.9% and 6.9% in the C-CAR-T group and R-CAR-T group, respectively (P = 0.697). The R-CAR-T group achieved a higher overall response rate (ORR) at the day 30 assessment (82.8% vs 45.2%, P = 0.0025). Further analyzing the outcomes, the R-CAR-T group presented a better 1-year progression-free survival (PFS) rate than the C-CAR-T group (46.9% vs 22.6%, P = 0.0356). Intriguingly, the bridging radiation regimen extremely improved the 6-month PFS (50.8% vs 16. 7%, P = 0.0369) and 1-year overall survival (OS) (56.3% vs 33.3%, P = 0.0236) rates in patients with bulky disease. The study also found that conducting radiotherapy as a bridging regimen was an independent factor that predicted better PFS (HR: 0.534, 95% CI: 0.289–0.987, P = 0.045). Our results provide and strengthen novel insights that the use of radiotherapy as a bridging strategy was demonstrated to reduce the incidence of severe CRS and improve the PFS of patients. In subgroup analysis, it was confirmed that radiotherapy can improve PFS and OS in patients with bulky disease. These findings open new avenues to improve the efficacy and safety of CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

Genetically engineered T and NK cells expressing a chimeric antigen receptor (CAR) are promising cytotoxic cells for the treatment of hematological malignancies and solid tumors. Despite the successful therapies using CAR-T cells, they have some disadvantages, such as cytokine release syndrome (CRS), neurotoxicity, or graft-versus-host-disease (GVHD). CAR-NK cells have lack or minimal cytokine release syndrome and neurotoxicity, but also multiple mechanisms of cytotoxic activity. NK cells are suitable for developing an "off the shelf" therapeutic product that causes little or no graft versus host disease (GvHD), but they are more sensitive to apoptosis and have low levels of gene expression compared to CAR-T cells. To avoid these adverse effects, further developments need to be considered to enhance the effectiveness of adoptive cellular immunotherapy. A promising approach to enhance the effectiveness of adoptive cellular immunotherapy is overcoming terminal differentiation or senescence and exhaustion of T cells. In this case, EVs derived from immune cells in combination therapy with drugs may be considered in the treatment of cancer patients, especially effector T and NK cells-derived exosomes with the cytotoxic activity of their original cells. [ABSTRACT FROM AUTHOR]

Cellular immunotherapy with CD19-directed chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape for aggressive B-cell non-Hodgkin lymphoma (B-NHL). Three CAR T-cell therapies are commercially available for the treatment of large B-cell lymphoma. This article reviews a case study to highlight a typical treatment journey for a patient with relapsed large B-cell lymphoma undergoing cellular immunotherapy, including treatment timeline and toxicities, as well as implications for advanced practice providers caring for patients with B-NHL. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptor T cells (CAR T-cells) are engineered T cells that target tumor-associated antigens. CAR T-cell therapy is a novel developed immunotherapy initially for destroying hematological malignancies. Its great success in clinical practice of hematological malignancies encourages oncologists and scientists to use CAR T-cells for the treatment of solid cancers. However, the efficacy of CAR T-cells in solid tumors is not as good as expected in hematological malignancies. In this review, we summarized the efficacy, safety, and challenges of CAR T-cell therapy in the clinical management of solid tumors. We also discussed the potential strategies currently applied to improve the efficacy and safety of CAR T-cell therapy in solid tumors, and finally prospected the future study direction for CAR T-cell therapy. Immunotherapy has been the fifth pillar of cancer treatment in the past decade. Chimeric antigen receptor (CAR) T-cell therapy is a newly designed adoptive immunotherapy that is able to target and further eliminate cancer cells by engaging with MHC-independent tumor-antigens. CAR T-cell therapy has exhibited conspicuous clinical efficacy in hematological malignancies, but more than half of patients will relapse. Of note, the efficacy of CAR T-cell therapy has been even more disappointing in solid tumors. These challenges mainly include (1) the failures of CAR T-cells to treat highly heterogeneous solid tumors due to the difficulty in identifying unique tumor antigen targets, (2) the expression of target antigens in non-cancer cells, (3) the inability of CAR T-cells to effectively infiltrate solid tumors, (4) the short lifespan and lack of persistence of CAR T-cells, and (5) cytokine release syndrome and neurotoxicity. In combination with these characteristics, the ideal CAR T-cell therapy for solid tumors should maintain adequate T-cell response over a long term while sparing healthy tissues. This article reviewed the status, clinical application, efficacy, safety, and challenges of CAR T-cell therapies, as well as the latest progress of CAR T-cell therapies for solid tumors. In addition, the potential strategies to improve the efficacy of CAR T-cells and prevent side effects in solid tumors were also explored. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the safety and efficacy of chimeric antigen receptor (CAR) disialoganglioside 2 (GD2)-specific (4SCAR-GD2) T cells for treatment of refractory and/or recurrent neuroblastoma (NB) in pediatric patients. Experimental design: A phase I clinical study using 4SCAR-GD2 T cells for the treatment of NB in pediatric patients was conducted. This study was registered at www.clinicaltrials.gov (NCT02765243). A lentiviral CAR with the signaling domains of CD28/4-1BB/CD3ζ-iCasp9 was transduced into activated T cells. The response to 4SCAR-GD2 T-cell treatment, and 4SCAR-GD2 T-cell expansion and persistence in patients were evaluated. Toxicities were determined based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Results: Twelve patients were enrolled and finally ten patients were included in this clinical trial which started from January 1, 2016, to August 1, 2017. These patients had progressive disease (PD) before CAR T-cell infusion. After 4SCAR-GD2 T-cell treatment, 6 (6/10) had stable disease (SD) at 6 months, and 4 (4/10) remained SD at 1 year and alive after 3–4 years of follow-up. Six patients died due to disease progression by the end of July 1, 2020. The median overall survival (OS) time was 25 months (95% CI, 0.00–59.43), and the median progression-free survival (PFS) time was 8 months (95% CI, 0.25–15.75). Grade 3 or 4 hematological toxicities were the common adverse events frequently occurred after fludarabine and cyclophosphamide (Flu/cy) chemotherapy. Grade 1–2 toxicities such as cytokine release syndrome (CRS) and neuropathic pain were common, but were transient and mild. Conclusions: The 4SCAR-GD2 T-cell therapy demonstrated antitumor effect and manageable toxicities, indicating its potential to benefit children with refractory and/or recurrent NB. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell‐based immunotherapy has been increasingly used in the clinic for cancer intervention over the past 5 years. CAR T‐cell therapy takes advantage of genetically‐modified T cells to express synthetic CAR molecules on the cell surface. To date, up to six CAR T cell therapy products have been approved by the Food and Drug Administration for the treatment of leukaemia, lymphoma, and multiple myeloma. In addition, hundreds of CAR‐T products are currently under clinical trials to treat solid tumours. In both the fundamental research and clinical applications, CAR T cell immunotherapy has achieved exciting progress with remarkable remission or suppression of cancers. However, CAR T cell‐based immunotherapy still faces significant safety issues, as exemplified by "on‐target off‐tumour" cytotoxicity due to lack of strict antigen specificity. In addition, uncontrolled massive activation of infused CAR T cells may create severe systemic inflammation with cytokine release syndrome and neurotoxicity. These challenges call for a need to combine nanotechnology and optogenetics with immunoengineering to develop spatiotemporally‐controllable CAR T cells, which enable wireless photo‐tunable activation of therapeutic immune cells to deliver personalised therapy in the tumour microenvironment. [ABSTRACT FROM AUTHOR]

Contemporary anticancer immunotherapy with chimeric antigen receptor T-cell (CAR-T) therapy has dramatically changed the treatment of many hematologic malignancies previously associated with poor prognosis. The clinical improvement and the survival benefit unveiled the risk of cardiotoxicity, ranging from minimal effects to severe cardiac adverse events, including death. Immunotherapy should also be proposed even in patients with pre-existing cardiovascular risk factors, thereby increasing the potential harm of cardiotoxicity. CAR-T therapy frequently results in cytokine release syndrome (CRS), and inflammatory activation is sustained by circulating cytokines that foster a positive feedback mechanism. Prompt diagnosis and treatment of CAR-T cardiotoxicity might significantly improve outcomes and reduce the burden associated with cardiovascular complications. Clinical and echocardiographic examinations are crucial to perform a tailored evaluation and follow-up during CAR-T treatment. This review aims to summarize the pathophysiology, clinical implications, and echocardiographic assessment of CAR-T-related cardiotoxicity to enlighten new avenues for future research. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR-T) is a relatively new treatment for pediatric leukemia and has been the focus of recent advancements. CAR is manufactured to express T cells through various ways such as using retroviruses, transposons and transposase, electroporation, and CRISPR (clustered regularly interspaced short palindromic repeats). Together, it provides flexibility since it recognizes proteins without the need of antigen processing and presentation, can recognize carbohydrates and lipids, and it has been proven to be cost-effective. Despite these benefits however, problems faced by this therapy include unrecognized tumor proteins possibly escaping the system, CAR T cell expression being transient, and the therapy being one of the most expensive cancer drug ever approved. As a result, recent progress has been ongoing where researchers have combined CAR-T cells with natural killer (NK) cells and different cytokines to maximize its efficacy and potency while limiting potential risks such as cytokine release syndrome. Consequently, these cells gained the ability to be universal—being able to be used to treat multiple patients, maintain viability for a longer period, and prevent relapse. [ABSTRACT FROM AUTHOR]

T-cell engagers (TCE) are cancer immunotherapies that have recently demonstrated meaningful benefit for patients with hematological malignancies and solid tumors. The anticipated widespread use of T cell engagers poses implementation challenges and highlights the need for guidance to anticipate, mitigate, and manage adverse events. By mobilizing T-cells directly at the contact of tumor cells, TCE mount an obligatory and immediate anti-tumor immune response that could result in diverse reactions and adverse events. Cytokine release syndrome (CRS) is the most common reaction and is largely confined to the first drug administrations during step-up dosage. Cytokine release syndrome should be distinguished from infusion related reaction by clinical symptoms, timing to occurrence, pathophysiological aspects, and clinical management. Other common reactions and adverse events with TCE are immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), infections, tumor flare reaction and cytopenias. The toxicity profiles of TCE and CAR-T cells have commonalities and distinctions that we sum-up in this review. As compared with CAR-T cells, TCE are responsible for less frequently severe CRS or ICANS. This review recapitulates terminology, pathophysiology, severity grading system and management of reactions and adverse events related to TCE. • Infusion related reactions and cytokine release syndromes (CRS) should be distinguished. • Cytokine release syndrome is the most common reaction with T-cell engagers (TCE). • Cytokine release syndromes is confined to first step-up dosages of T-cell engagers. • Most common toxicities with TCE are CRS, ICANS, infections, tumor flare reactions. • As compared with CAR-T cells, TCE generate less frequently severe CRS or ICANS. [ABSTRACT FROM AUTHOR]

Immunotherapy is blooming in recent years. However, this therapy needs to overcome off-target effects, cytokine release syndrome, and low responses in the 'cold' tumor environment. Herein, various combinations of immunotherapies and chemotherapies were proposed to transform 'cold' tumors into 'hot' tumors to enhance the efficacy of immunotherapies. In this study, we prepared a biocompatible ganetespib (GSP)-loaded PEGylated nanocarriers (NCs) with a thin-film method, which exhibited a small particle size (~220.6 nm), high drug loading (~5.8%), and good stability. We designed and produced the cluster of differentiation 3 (CD3)/programmed death ligand 1 (PD-L1)/methoxy-polyethylene glycol (mPEG) trispecific antibodies (TsAbs) as bispecific T-cell engagers (BiTEs) to non-covalently bind the GSP-NCs via anti-mPEG fragment and endowed the GSP-NCs with a targeting ability and immunotherapeutic potential to activate cytotoxic T cells. Decoration of the GSP-NCs with TsAbs (BiTEs-GSP-NCs) significantly promoted the cellular uptake and showed synergistic effects through respective anti-PD-L1 and anti-CD3 activation of T cell-mediated cytotoxicity. In vivo tumor-inhibition studies also showed that the BiTEs-GSP-NCs could inhibit tumor growth with the GSP chemodrug and increase T-cell infiltration. This study provides a promising drug delivery strategy for cancer immunochemotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Despite the impressive efficacy of chimeric antigen receptor (CAR) T-cell therapy, adverse effects, including cytokine release syndrome and neurotoxicity, impede its therapeutic application, thus making the modulation of CAR T-cell activity a priority. The destabilizing domain mutated from Escherichia coli dihydrofolate reductase (DHFR) is inherently unstable and degraded by proteasomes unless it is stabilized by its chemical ligand trimethoprim (TMP), a Food and Drug Administration-approved drug. Here the authors reveal a strategy to modulate CAR T-cell activity at the protein level by employing DHFR and TMP as a chemical switch system. First, the system was demonstrated to work in human primary T cells. To introduce the system to CAR T cells, DHFR was genetically fused to the carboxyl terminal of a third-generation CAR molecule targeting CD19 (CD19-CAR), constructing the CD19-CAR-DHFR fusion. The CD19-CAR-DHFR molecule level was shown to be modulated by TMP. Importantly, the incorporation of DHFR had no impact on the recognition specificity and normal function of the CAR molecule. Little adverse effect on cell proliferation and apoptosis was detected. It was proved that TMP could regulate cytokine secretion and the in vitro cytotoxicity of CD19-CAR-DHFR T cells. Furthermore, the in vivo anti-tumor efficacy was demonstrated to be controllable through the manipulation of TMP administration. The approach to control CD19-CAR also succeeded in 19-BBZ(71), another CD19-targeting CAR with a different structure. The proposed approach based on DHFR and TMP provides a facile strategy to bring CAR T-cell therapy under conditional user control, and the strategy may have the potential to be transplantable. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose: Two chimeric antigen receptor T-cell (CAR-T) therapies have been approved in the United States (USA) in 2017 and Europe (EU) in 2018: axicabtagene ciloleucel and tisagenlecleucel. They contain the patient's own T cells, which are extracted, genetically modified, and reinfused. Alongside the good efficacy results, the assessment of safety profile of these new therapies represents a great challenge. Our aim was to analyze the reports of the adverse drug reactions (ADR) after CAR-T administration as occurred in the real clinical setting. Methods: We performed a retrospective observational study, collecting all the reports in EU (EudraVigilance, EV) and US (FAERS) databases of ADRs regarding axicabtagene ciloleucel and tisagenlecleucel. Both descriptive and statistical analyses were performed, the latter by using Reporting Odds Ratio (ROR). Results: A total number of 1426 reports of suspected ADRs were retrieved in EudraVigilance and FAERS. Patients' reported age reflected the age range for which the drugs are approved (18–64 years for axicabtagene ciloleucel and patients aged under 25 years for tisagenlecleucel). The most reported event was cytokine release syndrome (CRS), 185 events for tisagenlecleucel and 462 for axicabtagene ciloleucel in FAERS and 137 and 498, respectively, in EudraVigilance. A disproportionality was found comparing axicabtagene ciloleucel with tisagenlecleucel for the above-mentioned event: EV ROR 2.47, 95% CI 2.22–2.74, FAERS 1.89, 1.70–2.10. Conclusion: CRS represents the major problem with the administration of CAR-T therapies. Our analysis has not revealed new ADRs; however, it supports the safety profile of CAR-T with new data from real clinical setting. [ABSTRACT FROM AUTHOR]

In recent decades, a new method of cellular immunotherapy was introduced based on engineering and empowering the immune effector cells. In this type of immunotherapy, the immune effector cells are equipped with chimeric antigen receptor (CAR) to specifically target cancer cells. In much of the trials and experiments, CAR-modified T cell immunotherapy has achieved very promising therapeutic results in the treatment of some types of cancers and infectious diseases. However, there are also some considerable drawbacks in the clinical application of CAR-T cells although much effort is in progress to rectify the issues. In some conditions, CAR-T cells initiate over-activated and strong immune responses, therefore, causing unexpected side-effects such as systemic cytokine toxicity (i.e., cytokine release syndrome), neurotoxicity, on-target, off-tumor toxicity, and graft-versus-host disease (GvHD). To overcome these limitations in CAR-T cell immunotherapy, NK cells as an alternative source of immune effector cells have been utilized for CAR-engineering. Natural killer cells are key players of the innate immune system that can destroy virus-infected cells, tumor cells, or other aberrant cells with their efficient recognizing capability. Compared to T cells, CAR-transduced NK cells (CAR-NK) have several advantages, such as safety in clinical use, non-MHC-restricted recognition of tumor cells, and renewable and easy cell sources for their preparation. In this review, we will discuss the recent preclinical and clinical studies, different sources of NK cells, transduction methods, possible limitations and challenges, and clinical considerations. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) modified T-cell therapy, a unique platform technology highlighting precision medicine through utilization of molecular biology and cell-based therapeutics has shown unprecedented rates in patients with hematological malignancies such as acute lymphocyte leukemia, non-Hodgkin's lymphoma and multiple myeloma (MM). With the approval of CD19-targeted CAR T-cells by the Food and Drug Administration in acute lymphoblastic leukemia (ALL) and NHL, this technology is positioned for aggressive expansion to combination therapeutic opportunities and proof of principle towards utility in other malignant disorders. However, despite the impressive results seen with hematological malignancies, CAR T-cells have shown limited efficacy in solid tumors with several unsuccessful preclinical studies. Regardless, these attempts have provided us with a better understanding of the imminent challenges specific to solid tumors even if they have not so far led to expanded clinical treatment opportunities outside ALL/NHL/MM. This review summarizes our current understanding of CAR T-cell mechanism of action, while presenting the major limitations of CAR T-cell derived treatments in solid tumors. We further discuss recent findings and present new potential strategies to overcome the challenges facing solid tumor targeting by CAR T-cell platforms. [ABSTRACT FROM AUTHOR]

The Food and Drug Administration has recently approved two autologous chimeric antigen receptor T-cell immunotherapies tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™) for patients with advanced lymphocytic malignancies. Both immunotherapies target the CD19-positive B-cell neoplasms. Kymriah™ is indicated for the treatment of relapsed or refractory acute lymphoblastic leukemia and large B-cell lymphoma. Yescarta™ is indicated for lymphoma only. Although the new therapy offers a promise for patients with advanced disease, it is associated with adverse events including neurotoxicity and cytokine release syndrome, which can be fatal and may require a high level of multidisciplinary supportive care. Due to the risks, both Kymriah™ and Yescarta™ are subject to Risk Evaluation and Mitigation Strategy (REMS) protocols. As active members of multidisciplinary clinical teams, pharmacists are likely to be responsible for the execution of Kymriah™ and Yescarta™ REMS programs. This manuscript describes foundational science and clinical knowledge of chimeric antigen receptor T-cell immunotherapies, common therapy-specific toxicities and REMS requirements for Kymriah™ and Yescarta™ in relation to practice of pharmacy. [ABSTRACT FROM AUTHOR]

Cytokine release syndrome (CRS) is a life threatening toxicity associated numerous immunotherapeutic techniques involving monoclonal antibodies, bispecific antibodies and adoptive T cell therapies. It is also referred as infusion reaction that results in release of large amount cytokines (Like IL-6, IFN-r, INF) from the target cells. Cytokines when released in excessive amounts into the circulation produces systemic symptoms like nausea, shills, fever, rashes, headache, hypotension, dyspenea etc. Most of the patients present mild to moderate symptoms which can be managed easily but some patients show life threatening symptoms. Studies have shown that immunosuppressive agents like corticosteroids and tocilizumab can reverse the toxicity of CRS, however such immunosuppression may limit the immunotherapeutic efficacy. Therefore specific precautions must be considered in such patients to present exacerbation of the complication. Thus this review is based on the overview of CRS which include etiology, mechanism and management of CRS, so that immunotherapeutic benefits can be maximized with minimum risk of complication. [ABSTRACT FROM AUTHOR]

Cellular therapy is a key tool to treat haematological malignancies. Over 40,000 allogeneic and autologous haematopoietic stem cell transplants (HSCTs) are performed annually across Europe. 1 Since 2017, a new T cell therapy, chimeric antigen receptor-T (CAR-T) cells have been licensed outside clinical trials. CAR-T cells have extremely potent antitumour activity, but also have a profile of toxic side effects not seen before. Cytokine release syndrome (CRS) and CAR-T cell-related encephalopathy syndrome (CRES) are common, predictable and potentially lethal side effects. Patients frequently require admission to intensive care, and management from a number of medical specialties. This exciting and powerful new therapy requires the formation of new multispecialty medical teams for safe delivery and to successfully manage the resultant complications. [ABSTRACT FROM AUTHOR]

Gene-engineered T-cell therapies have the potential to revolutionize the treatment of cancer. These therapies have shown exceptional clinical efficacy specifically in the field of B-cell malignancies and the first products (Kymriah™ and Yescarta™) have recently been approved in the United States for specific indications. The power of these treatments is also linked with a distinct set of toxicities both predicted and unpredicted, including off-tumor activity, cytokine release syndromes, and neurotoxicity, occasionally with fatal consequences. As these therapies begin to reach more patients, it is critical to develop the nonclinical tools to adequately determine the mechanisms driving these toxicities, to assess the safety risks of candidate products, and to develop strategies for safety management. [ABSTRACT FROM AUTHOR]

Therapeutic T cell engineering has recently garnered widespread interest because of the success of CD19 chimeric antigen receptor (CAR) therapy. CARs are synthetic receptors for antigen that redirect the specificity and reprogram the function of the T cells in which they are genetically introduced. CARs targeting CD19, a cell surface molecule found in most leukemias and lymphomas, have yielded high remission rates in patients with chemorefractory, relapsed disease, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. The toxicities of this treatment include B cell aplasia, cytokine release syndrome (CRS), and neurotoxicity. Although reversible in most instances, these toxicities may require specific medical interventions, including transfer to intensive care to treat severe CRS. Guidelines for managing these toxicities are emerging. The recent report of a nonhuman primate model for CRS is poised to help advance the management of this syndrome. Finally, new engineering modalities, based on the use of targeted nucleases like CRISPR, may further enhance the efficacy and safety of CAR T cells. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pediatric patients with relapsed and refractory acute lymphoblastic leukemia are more often being treated with chimeric antigen receptor (CAR) T-cell therapy. As with any new therapy, the management of this patient population has a unique set of challenges. The side effects of this therapy can range from mild to severe, with cytokine release syndrome being the most common reason for hospitalization.
 OBJECTIVES: This article presents common side effects, treatments, and challenges of caring for hospitalized patients who have received CAR T-cell therapy.
 METHODS: A case study is used to illustrate a patient’s inpatient hospitalization course after receiving CAR T-cell therapy, including the management of treatment-related toxicities.
 FINDINGS: As treatments emerge, nurses will be challenged with learning the associated side effects and toxicities. CAR T-cell therapy can result in a unique trajectory of potential symptoms and the potential for complete resolution of disease. [ABSTRACT FROM AUTHOR]

BACKGROUND: The introduction of chimeric antigen receptor (CAR) T-cell therapy has created challenges and opportunities for nurses. Clinical nurses must be educated on new treatment modalities to recognize toxicity symptoms and to support the therapy moving forward. 
OBJECTIVES: This article will discuss nursing leadership and interventions to standardize care and ensure patient safety while receiving CAR T cells. METHODS: Using evolving experience, an inter-professional team created standards of care and identified common toxicities and best practices for their management. Electronic documentation forms were designed, which led to the development of a new research infrastructure to care for patients.
 FINDINGS: The ability to safely manage patients on CAR T-cell treatments has improved. The new infrastructure supported clinicians and scientists in transforming the outcomes of diseases with bleak prognoses, which is possible only with strong nursing leadership. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pediatric patients with relapsed and refractory acute lymphoblastic leukemia are more often being treated with chimeric antigen receptor (CAR) T-cell therapy. As with any new therapy, the management of this patient population has a unique set of challenges. The side effects of this therapy can range from mild to severe, with cytokine release syndrome being the most common reason for hospitalization. OBJECTIVES: This article presents common side effects, treatments, and challenges of caring for hospitalized patients who have received CAR T-cell therapy. METHODS: A case study is used to illustrate a patient's inpatient hospitalization course after receiving CAR T-cell therapy, including the management of treatment-related toxicities. FINDINGS: As treatments emerge, nurses will be challenged with learning the associated side effects and toxicities. CART-cell therapy can result in a unique trajectory of potential symptoms and the potential for complete resolution of disease. [ABSTRACT FROM AUTHOR]

Highlights: [•] Cytokine release syndrome (CRS) is a fatal complication in CAR-T cell therapy. [•] CRS correlates with CAR structures, underlying diseases and cytokine gene polymorphisms. [•] CRS may be reduced by dose-escalation scheme, designing safer CARs and short-lived CAR-T cell infusion. [•] CRS can be controlled by cytokine-directed therapy using steroid and antagonists of cytokines. [ABSTRACT FROM AUTHOR]

Simple Summary: Bispecific antibodies are a very effective immunotherapy against different types of cancer since they activate T cells in the presence of tumor cells. However, they can cause severe side effects, such as a systemic inflammation called cytokine release syndrome. We aimed to clarify an important mechanism that causes cytokine release syndrome. In cocultures of T cells with endothelial cells or lymphoid cells, application of bispecific antibodies can induce T cell activation and cytokine release in the absence of tumor cells. By blocking the adhesion molecule CD18, this interaction is interrupted and the unwanted T cell activation is diminished. CD18 blockade, however, does not interfere with T cell activation when tumor cells are present. Therefore, CD18 blockade could prevent side effects of bispecific antibodies without decreasing the anti-tumor effect. T cell-recruiting bispecific antibodies (bsAbs) are successfully used for the treatment of cancer. However, effective treatment with bsAbs is so far hampered by severe side effects, i.e., potentially life-threatening cytokine release syndrome. Off-target T cell activation due to binding of bispecific CD3 antibodies to T cells in the absence of target cells may contribute to excessive cytokine release. We report here, in an in vitro setting, that off-target T cell activation is induced by bsAbs with high CD3 binding affinity and increased by endothelial- or lymphoid cells that act as stimulating bystander cells. Blocking antibodies directed against the adhesion molecules CD18/CD54 or CD2/CD58 markedly reduced this type of off-target T cell activation. CD18 blockade—in contrast to CD2—did not affect the therapeutic activity of various bsAbs. Since CD18 antibodies have been shown to be safely applicable in patients, blockade of this integrin holds promise as a potential target for the prevention of unwanted off-target T cell activation and allows the application of truly effective bsAb doses. [ABSTRACT FROM AUTHOR]

The article informs that chimeric antigen receptor (CAR) T-cell platform targeting CD7 induced a complete response (CR) with no minimal residual disease (MRD) in adults with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) who received treatment with the universal CAR T-cell therapy currently labeled GC027. It mentions that preliminary data demonstrate the feasibility of GC027, which does not require genetically engineering the drug from the patient's own T-cells.

Simple Summary: T cells modified with a chimeric antigen receptor (CAR) that targets BCMA, a protein expressed on malignant plasma cells, represent a novel treatment option for multiple myeloma. Despite initially eliminating the disease, the function of BCMA-directed CAR-T cells diminishes within a year of administration, leading to disease relapse. The aim of this research was to alter the cytokines used in the ex vivo expansion of anti-BCMA CAR-T cells, to avoid the development of an unfavorable phenotype that would impair in vivo function. We discovered that CAR-T cells expanded with IL-15 had reduced dysfunction and enhanced persistence compared to those grown with IL-2 or a combination of IL-15 and IL-7, which resulted in longer and improved anti-tumor responses in a mouse model. Therefore, the use of IL-15 alone in place of IL-2 or IL-15/IL-7 should be considered when designing CAR-T cell production protocols, to improve the duration of patient responses. Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the treatment of B-lymphoid malignancies. For multiple myeloma (MM), B-cell maturation antigen (BCMA)-targeted CAR-T cells have achieved outstanding complete response rates, but unfortunately, patients often relapse within a year of receiving the therapy. Increased persistence and reduced dysfunction are crucial features that enhance the durability of CAR-T cell responses. One of the factors that influence CAR-T cell in vivo longevity and loss of function, but which has not yet been extensively studied for BCMA-directed CAR-T cells, are the cytokines used during their production. We here compared the impact of IL-2, IL-15 and a combination of IL-15/IL-7 on the phenotype and function of ARI2h, an academic BCMA-directed CAR-T cell that is currently being administered to MM patients. For this study, flow cytometry, in vitro cytotoxicity assays and analysis of cytokine release were performed. In addition, ARI2h cells expanded with IL-2, IL-15, or IL-15/IL-7 were injected into MM tumor-bearing mice to assess their in vivo efficacy. We demonstrated that each of the cytokine conditions was suitable for the expansion of ARI2h cells, with clear in vitro activity. Strikingly, however, IL-15-produced ARI2h cells had improved in vivo efficacy and persistence. When explored further, it was found that IL-15 drove a less-differentiated ARI2h phenotype, ameliorated parameters related to CAR-T cell dysfunction, and lowered the release of cytokines potentially involved in cytokine release syndrome and MM progression. Moreover, we observed that IL-15 was less potent in inducing T cell senescence and DNA damage accumulation, both of which may contribute to an unfavorable CAR-T cell phenotype. These findings show the superiority of IL-15 to IL-2 and IL-15/IL-7 in the quality of anti-BCMA CAR-T cells, particularly their efficacy and persistence, and as such, could improve the duration of responses if applied to the clinical production of CAR-T cells for patients. [ABSTRACT FROM AUTHOR]

Immunoadoptive therapy with genetically modified T lymphocytes expressing chimeric antigen receptors (CARs) has revolutionized the treatment of patients with hematologic cancers. Although clinical outcomes in B-cell malignancies are impressive, researchers are seeking to enhance the activity, persistence, and also safety of CAR-T cell therapy—notably with a view to mitigating potentially serious or even life-threatening adverse events like on-target/off-tumor toxicity and (in particular) cytokine release syndrome. A variety of safety strategies have been developed by replacing or adding various components (such as OFF- and ON-switch CARs) or by combining multi-antigen-targeting OR-, AND- and NOT-gate CAR-T cells. This research has laid the foundations for a whole new generation of therapeutic CAR-T cells. Here, we review the most promising CAR-T cell safety strategies and the corresponding preclinical and clinical studies. [ABSTRACT FROM AUTHOR]

TNBC is an aggressive subtype with limited treatment options. We hypothesize that effective response against TNBC requires a coordinated approach that orchestrates both the innate and adaptive immune system. We further hypothesize that by orchestrating the activation of the entire immune system, we could accomplish immunogenic cell death with durable responses in this disease. We describe a first-in-human novel combination immunotherapy protocol of chemoradiation, cytokine-induced NK and T cell activation, checkpoint inhibition, and off-the-shelf high-affinity NK cell infusion. We instituted this novel immunotherapy protocol consisting of low-dose metronomic chemoradiation therapy, combined with a novel IgG1 Fc-engineered IL-15-complexed protein (NabFc-N803), adenoviral and yeast tumor-associated antigen vaccines (MUC1, brachyury, CEA), a PD-L1 checkpoint inhibitor, and off-the-shelf high-affinity NK cells (haNK). A phase 1b trial in pts with metastatic TNBC was initiated in 9 pts, 8 of whom had relapsed after two or more lines of prior therapy (3rd-line). All pts received this combination therapy instituted over a three-week cycle as outpatients. Safety was assessed and efficacy confirmed by CT. Nine pts have been treated to date. All pts received at least 3 treatment cycles. 8 grade ≥3 treatment-related AEs were observed in 4 pts to date, of which 2 had haNK-related SAEs consisting of fever and fatigue. No pts experienced cytokine release syndrome. To date, early efficacy results are as follows: a disease control rate (CR+PR+SD) of 78% (7/9 pts); ORR (PR+CR) of 56% (5/9 pts). Two pts (22%; 2/9) achieved a complete response (CR). To date, 8 pts are alive, and the duration of response ranges from 2 mo to over 12 mo. 7 pts remain on study to date. This first in human clinical trial of combination chemoradiation, cytokine fusion protein, checkpoint inhibitor, and NK cell therapy demonstrated a safe and tolerable immunotherapy protocol. Early efficacy data is encouraging with a 78% disease control rate, 56% ORR and 22% (2/9) CR in pts with metastatic TNBC, 2nd-line or greater. NCT03387085. NantKwest, Inc. NantKwest, Inc. P. Soon-Shiong: Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: NantCell; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: NantKwest; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: NantHealth; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: NantBio; Shareholder / Stockholder / Stock options: Celgene. S. Rabizadeh: Leadership role, Officer / Board of Directors: NantBio; Leadership role, Officer / Board of Directors: NantCell. J.H. Lee: Leadership role, Officer / Board of Directors: NantKwest; Leadership role, Officer / Board of Directors: NantCell. L. Sender: Leadership role, Officer / Board of Directors: NantKwest. F. Jones: Leadership role, Full / Part-time employment: NantCell; Leadership role, Officer / Board of Directors: Etubics. K. Niazi: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: NantBio. T. Seery: Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer. A. Rock: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: NantCell. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]