Tethered IL15-IL15Rα augments antitumor activity of CD19 CAR-T cells but displays long-term toxicity in an immunocompetent lymphoma mouse model.

BACKGROUND: Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation. METHODS: We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15Rα chimeric protein (CD19/mbIL15q CAR-T), in BALB/c mice challenged with A20 tumor cells as well as in NSG mice. RESULTS: Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer. CONCLUSION: Tethered IL15-IL15Rα augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15Rα expression could be considered to control this toxicity.

Advances in CAR-T-cell therapy in T-cell malignancies.

Significant advances have been made in chimeric antigen receptor T (CAR-T)-cell therapy for the treatment of recurrent or refractory B-cell hematologic malignancies. However, CAR-T-cell therapy has not yet achieved comparable success in the management of aggressive T-cell malignancies. This article reviews the challenges of CAR-T-cell therapy in treating T-cell malignancies and summarizes the progress of preclinical and clinical studies in this area. We present an analysis of clinical trials of CAR-T-cell therapies for the treatment of T-cell malignancies grouped by target antigen classification. Moreover, this review focuses on the major challenges encountered by CAR-T-cell therapies, including the nonspecific killing due to T-cell target antigen sharing and contamination with cell products during preparation. This review discusses strategies to overcome these challenges, presenting novel therapeutic approaches that could enhance the efficacy and applicability of CAR-T-cell therapy in the treatment of T-cell malignancies. These ideas and strategies provide important information for future studies to promote the further development and application of CAR-T-cell therapy in this field.

CAR-T cell therapy in advanced thyroid cancer: from basic to clinical.

The majority of patients with thyroid cancer can attain a favorable prognosis with a comprehensive treatment program based on surgical treatment. However, the current treatment options for advanced thyroid cancer are still limited. In recent years, chimeric antigen receptor-modified T-cell (CAR-T) therapy has received widespread attention in the field of oncology treatment. It has achieved remarkable results in the treatment of hematologic tumors. However, due to the constraints of multiple factors, the therapeutic efficacy of CAR-T therapy for solid tumors, including thyroid cancer, has not yet met expectations. This review outlines the fundamental structure and treatment strategies of CAR-T cells, provides an overview of the advancements in both preclinical investigations and clinical trials focusing on targets associated with CAR-T cell therapy in treating thyroid cancer, and discusses the challenges and solutions to CAR-T cell therapy for thyroid cancer. In conclusion, CAR-T cell therapy is a promising therapeutic approach for thyroid cancer, and we hope that our review will provide a timely and updated study of CAR-T cell therapy for thyroid cancer to advance the field.

Chimeric antigen receptor T-cell therapy for T-cell acute lymphoblastic leukemia.

Chimeric antigen receptor (CAR) T-cell therapy is a new and effective treatment for patients with hematologic malignancies. Clinical responses to CAR T cells in leukemia, lymphoma, and multiple myeloma have provided strong evidence of the antitumor activity of these cells. In patients with refractory or relapsed B-cell acute lymphoblastic leukemia (ALL), the infusion of autologous anti-CD19 CAR T cells is rapidly gaining standard-of-care status and might eventually be incorporated into frontline treatment. In T-ALL, however, leukemic cells generally lack surface molecules recognized by established CAR, such as CD19 and CD22. Such deficiency is particularly important, as outcome is dismal for patients with T-ALL that is refractory to standard chemotherapy and/or hematopoietic stem cell transplant. Recently, CAR T-cell technologies directed against T-cell malignancies have been developed and are beginning to be tested clinically. The main technical obstacles stem from the fact that malignant and normal T cells share most surface antigens. Therefore, CAR T cells directed against T-ALL targets might be susceptible to self-elimination during manufacturing and/or have suboptimal activity after infusion. Moreover, removing leukemic cells that might be present in the cell source used for CAR T-cell manufacturing might be problematic. Finally, reconstitution of T cells and natural killer cells after CAR T-cell infusion might be impaired. In this article, we discuss potential targets for CAR T-cell therapy of T-ALL with an emphasis on CD7, and review CAR configurations as well as early clinical results.

PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial.

Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CAR T cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805 .

Fully equipped CARs to address tumor heterogeneity, enhance safety, and improve the functionality of cellular immunotherapies.

Although adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has achieved unprecedented response rates in patients with certain hematological malignancies, this therapeutic modality is still far from fulfilling its remarkable potential, especially in the context of solid cancers. Antigen escape variants, off-tumor destruction of healthy tissues expressing tumor-associated antigens (TAAs), poor CAR-T cell persistence, and the occurrence of functional exhaustion represent some of the most prominent hurdles that limit CAR-T cell ability to induce long-lasting remissions with a tolerable adverse effect profile. In this review, we summarize the main approaches that have been developed to face such bottlenecks, including the adapter CAR (AdCAR) system, Boolean-logic gating, epitope editing, the modulation of cell-intrinsic signaling pathways, and the incorporation of safety switches to precisely control CAR-T cell activation. We also discuss the most pressing issues pertaining to the selection of co-stimulatory domains, with a focus on strategies aimed at promoting CAR-T cell persistence and optimal antitumor functionality.

Long-term Remissions Following CD20-Directed Chimeric Antigen Receptor-Adoptive T-cell Therapy.

Chimeric antigen receptor (CAR) T-cell therapy produces high response rates in refractory B-cell non-Hodgkin lymphoma, but long-term data are minimal to date. In this study, we present long-term follow-up of a pilot trial testing a CD20-targeting third-generation CAR in patients with relapsed B-cell lymphomas following cyclophosphamide-only lymphodepletion. Two of the three patients in the trial, with mantle cell lymphoma and follicular lymphoma, had remissions lasting more than 7 years, though they ultimately relapsed. The absence of B-cell aplasia in both patients suggested a lack of functional CAR T-cell persistence, leading to the hypothesis that endogenous immune responses were responsible for these long-term remissions. Correlative immunologic analyses supported this hypothesis, with evidence of new humoral and cellular antitumor immune responses proximal to clinical response time points. Collectively, our results suggest that CAR T-cell therapy may facilitate epitope spreading and endogenous immune response formation in lymphomas. Significance: Two of three patients treated with CD20-targeted CAR T-cell therapy had long-term remissions, with evidence of endogenous antitumor immune response formation. Further investigation is warranted to develop conditions that promote epitope spreading in lymphomas.

Current progress of CAR-T-cell therapy for patients with multiple myeloma.

Currently available chimeric antigen receptor (CAR)-engineered T-cell therapies targeting B-cell maturation antigen (BCMA), namely, idecabtagene vicleucel and ciltacabtagene autoleucel, have shown marked efficacy against relapsed and refractory multiple myeloma. However, further improvement in CAR-T-cell function is warranted as most patients treated with these products eventually relapse due to various mechanisms such as antigen loss and T-cell dysfunction or disappearance. Strategies for improving CAR-T-cell function include targeting of dual antigens, enhancing cell longevity through genetic modification, and eliminating the immunosuppressive tumor microenvironment. Serious side effects can also occur after CAR-T-cell infusions. Although understanding of the molecular pathogenesis of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome is growing, the unique movement disorder caused by BCMA-targeted therapy is less understood, and its molecular mechanisms must be further elucidated to establish better management strategies. In this article, we will review the current status of BCMA-targeting CAR-T-cell therapy. We will also highlight progress in the development of CAR-T cells targeting other antigens, as well as universal allogeneic CAR-T cells and bispecific antibodies.

Charting new paradigms for CAR-T cell therapy beyond current Achilles heels.

Chimeric antigen receptor-T (CAR-T) cell therapy has made remarkable strides in treating hematological malignancies. However, the widespread adoption of CAR-T cell therapy is hindered by several challenges. These include concerns about the long-term and complex manufacturing process, as well as efficacy factors such as tumor antigen escape, CAR-T cell exhaustion, and the immunosuppressive tumor microenvironment. Additionally, safety issues like the risk of secondary cancers post-treatment, on-target off-tumor toxicity, and immune effector responses triggered by CAR-T cells are significant considerations. To address these obstacles, researchers have explored various strategies, including allogeneic universal CAR-T cell development, infusion of non-activated quiescent T cells within a 24-hour period, and in vivo induction of CAR-T cells. This review comprehensively examines the clinical challenges of CAR-T cell therapy and outlines strategies to overcome them, aiming to chart pathways beyond its current Achilles heels.

CAR-T cell therapy: Efficacy in management of cancers, adverse effects, dose-limiting toxicities and long-term follow up.

Chimeric Antigen Receptor T-cell (CAR-T) therapy has emerged as a groundbreaking and highly promising approach for the management of cancer. This paper reviews the efficacy of CAR-T therapy in the treatment of various hematological malignancies, also, with a mention of its effect on solid tumors, for which they have not received FDA approval yet. Different common and uncommon side effects are also discussed in this paper, with attention to the effect of each drug separately. By reviewing the recommendations of the FDA for CAR-T therapy research, we have extensively discussed dose-limiting toxicities. This further highlights the need for precise dosing strategies, striking a balance between therapeutic benefits and potential risks. Additionally, we reviewed the long-term follow-up of patients receiving CAR-T therapy to gain valuable insights into response durability and late-onset effects.

Engineered CAR-T cells: An immunotherapeutic approach for cancer treatment and beyond.

Chimeric Antigen Receptor (CAR) T cell therapy is a type of adoptive immunotherapy that offers a promising avenue for enhancing cancer treatment since traditional cancer treatments like chemotherapy, surgery, and radiation therapy have proven insufficient in completely eradicating tumors, despite the relatively positive outcomes. It has been observed that CAR-T cell therapy has shown promising results in treating the majority of hematological malignancies but also have a wide scope for other cancer types. CAR is an extra receptor on the T-cell that helps to increase and accelerate tumor destruction by efficiently activating the immune system. It is made up of three domains, the ectodomain, transmembrane, and the endodomain. The ectodomain is essential for antigen recognition and binding, whereas the co-stimulatory signal is transduced by the endodomain. To date, the Food and Drug Administration (FDA) has granted approval for six CAR-T cell therapies. However, despite its remarkable success, CAR-T therapy is associated with numerous adverse events and has certain limitations. This chapter focuses on the structure and function of the CAR domain, various generations of CAR, and the process of CAR-T cell development, adverse effects, and challenges in CAR-T therapy. CAR-T cell therapy also has scopes in other disease conditions which include systemic lupus erythematosus, multiple sclerosis, and myocardial fibrosis, etc.

Off-the-shelf CAR-T cell therapies for relapsed or refractory B-cell malignancies: latest update from ASH 2023 annual meeting.

Currently, many off-the-shelf chimeric antigen receptor (CAR)-T cell products are under investigation for the treatment of relapsed or refractory (R/R) B-cell neoplasms. Compared with autologous CAR-T cell therapy, off-the-shelf universal CAR-T cell therapies have many potential benefits, such as immediate accessibility for patients, stable quality due to industrialized manufacturing and additional infusions of CAR-T cells with different targets. However, critical challenges, including graft-versus-host disease and CAR-T cell elimination by the host immune system, still require extensive research. The most common technological approaches involve modifying healthy donor T cells via gene editing technology and altering different types of T cells. This article summarizes some of the latest data from preclinical and clinical studies of off-the-shelf CAR-T cell therapies in the treatment of R/R B-cell malignancies from the 2023 ASH Annual Meeting (ASH 2023).

Engineered CD47 protects T cells for enhanced antitumour immunity.

Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.

INSPIRED Symposium Part 5: Expanding the Use of CAR T Cells in Children and Young Adults.

Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable efficacy in relapsed/refractory (r/r) B cell malignancies, including in pediatric patients with acute lymphoblastic leukemia (ALL). Expanding this success to other hematologic and solid malignancies is an area of active research and, although challenges remain, novel solutions have led to significant progress over the past decade. Ongoing clinical trials for CAR T cell therapy for T cell malignancies and acute myeloid leukemia (AML) have highlighted challenges, including antigen specificity with off-tumor toxicity and persistence concerns. In T cell malignancies, notable challenges include CAR T cell fratricide and prolonged T cell aplasia, which are being addressed with strategies such as gene editing and suicide switch technologies. In AML, antigen identification remains a significant barrier, due to shared antigens across healthy hematopoietic progenitor cells and myeloid blasts. Strategies to limit persistence and circumvent the immunosuppressive tumor microenvironment (TME) created by AML are also being explored. CAR T cell therapies for central nervous system and solid tumors have several challenges, including tumor antigen heterogeneity, immunosuppressive and hypoxic TME, and potential for off-target toxicity. Numerous CAR T cell products have been designed to overcome these challenges, including "armored" CARs and CAR/T cell receptor (TCR) hybrids. Strategies to enhance CAR T cell delivery, augment CAR T cell performance in the TME, and ensure the safety of these products have shown promising results. In this manuscript, we will review the available evidence for CAR T cell use in T cell malignancies, AML, central nervous system (CNS), and non-CNS solid tumor malignancies, and recommend areas for future research.

The dilemmas and possible solutions for CAR-T cell therapy application in solid tumors.

Chimeric antigen receptor T (CAR-T) cell therapy, as an adoptive immunotherapy, is playing an increasingly important role in the treatment of malignant tumors. CAR-T cells are referred to as "living drugs" as they not only target tumor cells directly, but also induce long-term immune memory that has the potential to provide long-lasting protection. CD19.CAR-T cells have achieved complete response rates of over 90 % for acute lymphoblastic leukemia and over 60 % for non-Hodgkin's lymphoma. However, the response rate of CAR-T cells in the treatment of solid tumors remains extremely low and the side effects potentially severe. In this review, we discuss the limitations that the solid tumor microenvironment poses for CAR-T application and the solutions that are being developed to address these limitations, in the hope that in the near future, CAR-T cell therapy for solid tumors can attain the same success rates as are now being seen clinically for hematological malignancies.

Potential and pitfalls of repurposing the CAR-T cell regimen for the treatment of autoimmune disease.

Chimeric antigen receptors (CARs) are synthetic proteins designed to direct an immune response toward a specific target and have been used in immunotherapeutic applications through the adoptive transfer of T cells genetically engineered to express CARs. This technology received early attention in oncology with particular success in treatment of B cell malignancies leading to the launch of numerous successful clinical trials and the US Food and Drug Administration approval of several CAR-T-based therapies. Many CAR-T constructs have been employed, but have always been administered following a lymphodepletion regimen. The success of CAR-T cell treatment in targeting malignant B cells has led many to consider the potential for using these regimens to delete pathogenic B cells in autoimmune diseases. Preliminary results have suggested efficacy, but the sample size remains small, controlled trials have not been done, the role of immunodepletion has not been established, the most effective CAR-T constructs have not been identified and the most appropriate patient subsets for treatment have not been established.

Immunotherapy with genetically engineered T cells holds promise for the treatment of nonmalignant diseases in the dog.

The ability to genetically redirect the antigenic specificity of T cells using chimeric antigen receptors (CAR) has led to unprecedented durable clinical remissions in human patients with relapsed/refractory hematological malignancies. This remarkable advance in successful immune cell engineering has now led to investigations into the application of CAR-T-cell technology to treat nonmalignant diseases. The use of CAR-T cells to target and eliminate specific cell subsets involved in the pathogenesis of autoimmunity, fibrosis, senescence, and infectious disease represents a new direction for adoptive cell therapies. While the use of CAR-T cells for nonmalignant disease is still in its infancy, early reports of dramatic clinical responses to CAR-T cells targeting CD19+ B cells in patients with severe autoimmune disease raise the possibility that this approach could lead to durable remissions, eliminating the need for ongoing conventional immunosuppressive therapies. Excitingly, nonmalignant disease processes that may be addressed by CAR-T-cell therapy in humans also occur in our canine populations. Given that technologies for developing canine CAR constructs are now available, robust protocols have been described for generating canine CAR-T cells, and experience is being gathered with their clinical use in oncology, it is anticipated that CAR-T cells will soon enter the veterinary clinics for the treatment of debilitating nonmalignant diseases. Here, we provide a broad overview of CAR-T-cell therapies for nonmalignant diseases and extrapolate these advances into the veterinary space, highlighting areas in which canine CAR-T cells are poised to enter the clinics for the treatment of nonmalignant disease.