CAR T-cell therapy in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive leukemic malignancy that affects myeloid lineage progenitors. Relapsed or refractory AML patients continue to have poor prognoses, necessitating the development of novel therapy alternatives. Adoptive T-cell therapy with chimeric antigen receptors (CARs) is an intriguing possibility in the field of leukemia treatment. Chimeric antigen receptor T-cell therapy is now being tested in clinical trials (mostly in phase I and phase II) using AML targets including CD33, CD123, and CLL-1. Preliminary data showed promising results. However, due to the cellular and molecular heterogeneity of AML and the co-expression of some AML targets on hematopoietic stem cells, these clinical investigations have shown substantial "on-target off-tumor" toxicities, indicating that more research is required. In this review, the latest significant breakthroughs in AML CAR T cell therapy are presented. Furthermore, the limitations of CAR T-cell technology and future directions to overcome these challenges are discussed.

Generating advanced CAR-based therapy for hematological malignancies in clinical practice: targets to cell sources to combinational strategies.

Chimeric antigen receptor T (CAR-T) cell therapy has been a milestone breakthrough in the treatment of hematological malignancies, offering an effective therapeutic option for multi-line therapy-refractory patients. So far, abundant CAR-T products have been approved by the United States Food and Drug Administration or China National Medical Products Administration to treat relapsed or refractory hematological malignancies and exhibited unprecedented clinical efficiency. However, there were still several significant unmet needs to be progressed, such as the life-threatening toxicities, the high cost, the labor-intensive manufacturing process and the poor long-term therapeutic efficacy. According to the demands, many researches, relating to notable technical progress and the replenishment of alternative targets or cells, have been performed with promising results. In this review, we will summarize the current research progress in CAR-T eras from the "targets" to "alternative cells", to "combinational drugs" in preclinical studies and clinical trials.

ReCARving the future: bridging CAR T-cell therapy gaps with synthetic biology, engineering, and economic insights.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, offering remarkable remission rates in otherwise refractory conditions. However, its expansion into broader oncological applications faces significant hurdles, including limited efficacy in solid tumors, safety concerns related to toxicity, and logistical challenges in manufacturing and scalability. This review critically examines the latest advancements aimed at overcoming these obstacles, highlighting innovations in CAR T-cell engineering, novel antigen targeting strategies, and improvements in delivery and persistence within the tumor microenvironment. We also discuss the development of allogeneic CAR T cells as off-the-shelf therapies, strategies to mitigate adverse effects, and the integration of CAR T cells with other therapeutic modalities. This comprehensive analysis underscores the synergistic potential of these strategies to enhance the safety, efficacy, and accessibility of CAR T-cell therapies, providing a forward-looking perspective on their evolutionary trajectory in cancer treatment.

Engineered T cells for Colorectal Cancer.

Colorectal cancer (CRC) is a major contributor to global cancer incidence and mortality. Conventional treatments have limitations; hence, innovative approaches are imperative. Recent advancements in cancer research have led to the development of personalized targeted therapies and immunotherapies. Immunotherapy, in particular, T cell-based therapies, exhibited to be promising in enhancing cancer treatment outcomes. This review focuses on the landscape of engineered T cells as a potential option for the treatment of CRC. It highlights the approaches, challenges and current advancements in this field. As the understanding of molecular mechanisms increases, engineered T cells hold great potential in revolutionizing cancer treatment. To fully explore their safety efficacy in improving patient outcomes, further research and clinical trials are necessary.

Colorectal cancer (CRC) is a significant cause of cancer cases and cancer-related deaths globally. Current treatments for CRC have limitations; hence, there is a need for new and innovative approaches. Recent progress in cancer research has led to the development of personalized targeted therapies and immunotherapies, that is, treatments that use the body's immune system to fight cancer. T cell-based therapy is a type of immunotherapy that has shown promising outcomes in cancer treatment. This therapy involves modifying a type of immune cell called T cells to specifically target cancer cells. In this review, the focus is on the landscape of engineered T cells as a potential option for the treatment of CRC, as well as their challenges and current advancements. Generally, additional research and clinical trials are needed to fully explore its safety and efficacy in improving patient outcomes.

Acute T-cell lymphoblastic leukemia: chimeric antigen receptor technology may offer a new hope.

Acute lymphoblastic leukemia (ALL) is a prevalent malignancy affecting the hematopoietic system, encompassing both B-cell ALL (B-ALL) and T-cell ALL (T-ALL). T-ALL, characterized by the proliferation of T-cell progenitors in the bone marrow, presents significant treatment challenges, with patients often experiencing high relapse rates and poor long-term survival despite advances in chemotherapy and hematopoietic stem cell transplantation (HSCT). This review explores the pathogenesis and traditional treatment strategies of T-ALL, emphasizing the promising potential of chimeric antigen receptor (CAR) technology in overcoming current therapeutic limitations. CAR therapy, leveraging genetically modified immune cells to target leukemia-specific antigens, offers a novel and precise approach to T-ALL treatment. The review critically analyzes recent developments in CAR-T and CAR-NK cell therapies, their common targets, optimization strategies, clinical outcomes, and the associated challenges, providing a comprehensive overview of their clinical prospects in T-ALL treatment.

Chimeric antigen receptor (CAR) T-cell therapy: Harnessing extracellular vesicles for enhanced efficacy.

A cutting-edge approach in cell-based immunotherapy for combating resistant cancer involves genetically engineered chimeric antigen receptor T (CAR-T) lymphocytes. In recent years, these therapies have demonstrated effectiveness, leading to their commercialization and clinical application against certain types of cancer. However, CAR-T therapy faces limitations, such as the immunosuppressive tumour microenvironment (TME) that can render CAR-T cells ineffective, and the adverse side effects of the therapy, including cytokine release syndrome (CRS). Extracellular vesicles (EVs) are a diverse group of membrane-bound particles released into the extracellular environment by virtually all cell types. They are essential for intercellular communication, transferring cargoes such as proteins, lipids, various types of RNAs, and DNA fragments to target cells, traversing biological barriers both locally and systemically. EVs play roles in numerous physiological processes, with those from both immune and non-immune cells capable of modulating the immune system through activation or suppression. Leveraging this capability of EVs to enhance CAR-T cell therapy could represent a significant advancement in overcoming its current limitations. This review examines the current landscape of CAR-T cell immunotherapy and explores the potential role of EVs in augmenting its therapeutic efficacy.

CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors.

In the past decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers, demonstrating remarkable efficacy in relapsed/refractory hematological malignancies in both pediatric and adult patients. CAR-natural killer (CAR-NK) cell complements CAR-T cell therapy by offering several distinct advantages. CAR-NK cells do not require HLA compatibility and exhibit low safety concerns. Moreover, CAR-NK cells are conducive to "off-the-shelf" therapeutics, providing significant logistic advantages over CAR-T cells. Both CAR-T and CAR-NK cells have shown consistent and promising results in hematological malignancies. However, their efficacy against solid tumors remains limited due to various obstacles including limited tumor trafficking and infiltration, as well as an immuno-suppressive tumor microenvironment. In this review, we discuss the recent advances and current challenges of CAR-T and CAR-NK cell immunotherapies, with a specific focus on the obstacles to their application in solid tumors. We also analyze in depth the advantages and drawbacks of CAR-NK cells compared to CAR-T cells and highlight CAR-NK CAR optimization. Finally, we explore future perspectives of these adoptive immunotherapies, highlighting the increasing contribution of cutting-edge biotechnological tools in shaping the next generation of cellular immunotherapy.

Prospects of Synergy: Local Interventions and CAR T Cell Therapy in Solid Tumors.

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.

CD5 deletion enhances the antitumor activity of adoptive T cell therapies.

Most patients treated with US Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.

Anti-BCMA/GPRC5D bispecific CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, single-centre, phase 1 trial.

BACKGROUND: Some challenges still exist with single-target B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapies due to variable or negative BCMA expression, although they have yielded remarkable efficacy in relapsed or refractory multiple myeloma. We developed anti-BCMA/GPRC5D bispecific CARs to mitigate the limitations and potentiate the functions of CAR T cells. METHODS: This single-arm, phase 1 trial was conducted at the Affiliated Hospital of Xuzhou Medical University (Xuzhou, China). The trial enrolled patients aged 18-75 years with relapsed or refractory multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0-3. Anti-BCMA/GPRC5D bispecific CAR T cells were administered at 0·5 × 106, 1·0 × 106, 2·0 × 106, and 4·0 × 106 CAR T cells per kg in the dose-escalation phase, with additional patients included at the dose selected for the dose-expansion phase. The primary endpoint was safety, which included dose-limiting toxicity and maximum tolerated dose. Activity was also evaluated as a secondary endpoint. The maximum tolerated dose was chosen for the dose-expansion phase. Safety and activity analyses were done in all patients who received anti-BCMA/GPRC5D bispecific CAR T cells as defined in the protocol. This trial is registered with ClinicalTrials.gov (NCT05509530) and is complete. FINDINGS: Between Sept 1, 2022, and Nov 3, 2023, 24 patients were enrolled and underwent apheresis. Three patients were excluded after apheresis (two patients discontinued due to rapid disease progression and one patient was withdrawn because of failed manufacture of CAR T cells), so 21 patients were infused with anti-BCMA/GPRC5D bispecific CAR T cells. Median follow-up was 5·8 months (IQR 5·2-6·7). Median age was 62 years (IQR 56-67). Eight (38%) patients were male, and 13 (62%) female. All patients were Chinese. At the 4·0 × 106 CAR T cells per kg dose, two patients had dose-limiting toxicities, of whom one died of subarachnoid haemorrhage (which was not considered to be related to the study treatment). The maximum tolerated dose was identified as 2·0 × 106 CAR T cells per kg. The most common grade 3 or worse adverse events were haematological toxicities in 19 (90%) patients (except lymphopenia). 15 (71%) patients had cytokine release syndrome, of which all cases were grade 1 or 2. One case of grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in a patient who received 4·0 × 106 CAR T cells per kg. No ICANS or grade 3 or worse organ toxicities were observed in patients who received 0·5-2·0 × 106 CAR T cells per kg. The overall response rate was 86% (18 of 21 patients), with 13 (62%) patients having a complete response or better, and 17 (81%) patients having measurable residual disease negativity. Of the 12 patients who received 2·0 × 106 CAR T cells per kg (three in the dose-escalation phase and an addition nine in the dose-expansion phase), the overall response rate was 92% (11 of 12 patients) with nine (75%) patients having a complete response or better. INTERPRETATION: Anti-BCMA/GPRC5D bispecific CAR T cells show a good safety profile and encouraging activity in patients with relapsed or refractory multiple myeloma. FUNDING: National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Adoptive transfer of personalized neoantigen-reactive TCR-transduced T cells in metastatic colorectal cancer: phase 2 trial interim results.

Adoptive cell transfer (ACT) with neoantigen-reactive T lymphocytes can mediate cancer regression. Here we isolated unique, personalized, neoantigen-reactive T cell receptors (TCRs) from tumor-infiltrating lymphocytes of patients with metastatic gastrointestinal cancers and incorporated the TCR α and ß chains into gamma retroviral vectors. We transduced autologous peripheral blood lymphocytes and adoptively transferred these cells into patients after lymphodepleting chemotherapy. In a phase 2 single-arm study, we treated seven patients with metastatic, mismatch repair-proficient colorectal cancers who had progressive disease following multiple previous therapies. The primary end point of the study was the objective response rate as measured using RECIST 1.1, and the secondary end points were safety and tolerability. There was no prespecified interim analysis defined in this study. Three patients had objective clinical responses by RECIST criteria including regressions of metastases to the liver, lungs and lymph nodes lasting 4 to 7 months. All patients received T cell populations containing ≥50% TCR-transduced cells, and all T cell populations were polyfunctional in that they secreted IFNγ, GM-CSF, IL-2 and granzyme B specifically in response to mutant peptides compared with wild-type counterparts. TCR-transduced cells were detected in the peripheral blood of five patients, including the three responders, at levels ≥10% of CD3+ cells 1 month post-ACT. In one patient who responded to therapy, ~20% of CD3+ peripheral blood lymphocytes expressed transduced TCRs more than 2 years after treatment. This study provides early results suggesting that ACT with T cells genetically modified to express personalized neoantigen-reactive TCRs can be tolerated and can mediate tumor regression in patients with metastatic colorectal cancers. ClinicalTrials.gov registration: NCT03412877 .

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.

Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results.

Claudin18.2 (CLDN18.2) is highly expressed with the development of various malignant tumors, especially gastrointestinal cancers, and is emerging as a new target for cancer treatment. Satricabtagene autoleucel (satri-cel)/CT041 is an autologous chimeric antigen receptor (CAR) T cell targeting CLDN18.2, and the interim results of the CT041-CG4006 trial were reported in June 2022. Here we present the final results of this single-arm, open-label, phase 1 trial, which evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced gastrointestinal cancers. This trial included a dose-escalation stage (n = 15) and a dose-expansion stage in four different cohorts (total n = 83): cohort 1, satri-cel monotherapy in 61 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 2, satri-cel plus anti-PD-1 therapy in 15 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 3, satri-cel as sequential treatment after first-line therapy in five patients with gastrointestinal cancers; and cohort 4, satri-cel monotherapy in two patients with anti-CLDN18.2 monoclonal antibody-refractory gastric cancer. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics and immunogenicity. A total of 98 patients received satri-cel infusion, among whom 89 were dosed with 2.5 × 108, six with 3.75 × 108 and three with 5.0 × 108 CAR T cells. Median follow-up was 32.4 months (95% confidence interval (CI): 27.3, 36.5) since apheresis. No dose-limiting toxicities, treatment-related deaths or immune effector cell-associated neurotoxicity syndrome were reported. Cytokine release syndrome occurred in 96.9% of patients, all classified as grade 1-2. Gastric mucosal injuries were identified in eight (8.2%) patients. The overall response rate and disease control rate in all 98 patients were 38.8% and 91.8%, respectively, and the median progression-free survival and overall survival were 4.4 months (95% CI: 3.7, 6.6) and 8.8 months (95% CI: 7.1, 10.2), respectively. Satri-cel demonstrates therapeutic potential with a manageable safety profile in patients with CLDN18.2-positive advanced gastrointestinal cancer. ClinicalTrials.gov identifier: NCT03874897 .

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 .