T-cell Therapy Research Articles

Redefining chimeric antigen receptor T-cell (CAR-T) regulation: China's responses to address secondary cancer risks of CAR-T therapy.

Since the United States Food and Drug Administration (FDA) approved the first chimeric antigen receptor T-cell (CAR-T) therapy in 2017, it has marked a major breakthrough in cancer treatment, leading to a surge in global research and applications in this field. In recent years, China has made rapid progress, quickly catching up through heavy investment in CAR-T construction, preparation processes, and treatment strategies. China's CAR-T therapy market is driven by substantial pharmaceutical investment targeting its vast population, yet high therapy costs remain uncovered by basic medical insurance. In November 2023, FDA issued a warning about the risk of secondary cancers in patients undergoing CAR-T therapy, sparking global concern. In fact, the China National Medical Products Administration (NMPA) preemptively implemented a series of measures to address the safety concerns of CAR-T therapy, emphasizing the risk of secondary cancers and advising lifelong monitoring as part of the approval process for CAR-T products. Nevertheless, additional regulatory measures are needed to address emerging risks, particularly the threat of secondary cancers. The authors believe that raising the standards for Investigational New Drug (IND) approval and establishing a dynamic reporting and feedback system based on real-world data will strengthen regulatory oversight and support the sustainable growth of the CAR-T industry in China.

Metabolic tumor volume response after bridging therapy determines chimeric antigen receptor T-cell outcomes in large B cell lymphoma.

Greater disease burden is a well-established predictor of poorer outcomes following chimeric antigen receptor T-cell therapy (CART). While bridging therapy (BT) is widely used between leukapheresis and CAR T infusion, limited data has evaluated the impact of BT on CART outcomes. In this study, we hypothesized that the quantitative dynamics of radiomic cytoreduction during bridging are prognostic. Patients with large B-cell lymphoma (LBCL) treated with CD19-CART from 2016-2022 were included. Metabolic tumor volume (MTV) was determined for all patients on pre-leukapheresis PET and on post-BT/pre-infusion PET in those who received BT. Patients were stratified into 'High' and 'Low' disease burden using an MTV cutpoint of 65.4cc established by maximally selected log-rank statistic for progression free survival (PFS). Of 191 patients treated with CART, 144 (75%) received BT. In the BT cohort, 56% had any reduction in MTV post-BT. On multivariate analysis, MTV trajectory across the bridging period remained significantly associated with PFS (p<0.001), however notably patients with improved MTV (High->Low) had equivalent PFS compared to those with initially and persistently low MTV (Low->Low) (HR for High->Low MTV: 2.74, CI: 0.82-9.18). There was a reduction in any Grade ICANS in the High->Low MTV cohort as compared to High->High (13 vs. 41%, p=0.05). This is the first study to use radiomics to quantify disease burden pre- and post-BT in a large real world LBCL cohort. We demonstrate that effective BT can enable initially high-disease burden patients to achieve post-CART outcomes comparable to low-disease burden patients.

B-Cell Maturation Antigen-Directed Immunotherapies for the Treatment of Relapsed/Refractory Multiple Myeloma: A Review of the Literature and Implications for Clinical Practice.

To review the pharmacology, efficacy, safety, dosing and administration, and relevance to patient care and clinical practice of B-cell maturation antigen (BCMA) directed immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAb), for the management of relapsed/refractory multiple myeloma (RRMM). A literature review of PubMed (1966 to July 2024) was conducted using the keywords idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, elranatamab, and multiple myeloma. Data was also obtained from unpublished meeting abstracts and prescribing information. All relevant published articles, unpublished abstracts, and prescribing information on anti-BCMA immunotherapies for the treatment of RRMM were reviewed. Idecabtagene vicleucel and ciltacabtagene autoleucel are BCMA-directed CAR-T cell therapies that have been compared to standard of care (SOC) regimens for MM in early relapse in the phase III trials KarMMa-3 and CARTITUDE-4, respectively. Both studies demonstrated a significantly improved in response rates, depth of response, and progression-free survival compared to SOC. BsAbs teclistamab and elranatamab have been evaluated in the phase II trials MajesTEC-1 and MagnetisMM-3, respectively. Overall response rates of 63 and 61% were observed with teclistamab and elranatamab, respectively, in a population of patients with heavily pretreated RRMM. BCMA-directed immunotherapies have demonstrated efficacy in the treatment of RRMM. Safety issues with BCMA-directed immunotherapies include cytokine release syndrome, neurotoxicity, infections, and cytopenias. Operational challenges and issues with access to care exist with these therapies as they may be limited to institutions with the infrastructure to safely administer and monitor patients for toxicities. BCMA-directed immunotherapies represent an important advancement in the management of RRMM and have significantly added to the available treatment options for this disease.

When Chinese patients with plasma cell disorders encountered the nationwide Omicron outbreak (December 2022): a real-world multicenter and multiregional study.

This study aims to assess the impact of the nationwide Omicron outbreak in December 2022 on Chinese patients with plasma cell disorders (PCD), focusing on the clinical characteristics of PCD patients with COVID-19 and the risk factors contributing to adverse clinical courses (severity and hospitalization) and outcomes. A multicenter retrospective study was performed from December 1, 2022, to January 19, 2023. The study population includes 404 PCD patients, divided into a COVID-19 group (n = 342) and an uninfected group (n = 62). The frequency of COVID-19 infection was 84.7% (342/404), and 16.4% (56/342) were severe COVID-19. Among the 277 patients with complete follow-up, 2 deaths (0.7%) were reported, while 231 (83.4%) recovered from COVID-19. Age > 65 (P = 0.02) and prior anti-CD38 monoclonal antibody (mAb) treatment within six months (P = 0.03) were independent risk factors for severe infection. Additionally, previous chimeric antigen receptor T-cell (CAR-T) therapy within six months was correlated with a higher risk of hospitalization (P = 0.04) and prolonged recovery time (P = 0.03). No significant protective effect of vaccination on infection or severe infection was observed (P > 0.05). The latest Omicron outbreak results in higher rates of severe infection and mortality in PCD patients compared with the general population in China, highlighting the need to protect this vulnerable population during the pandemic. Recent use of anti-CD38 mAb and CAR-T therapy are associated with poorer clinical courses and outcomes of PCD patients with COVID-19.

Cardiovascular Events After Chimeric Antigen Receptor T-Cell Therapy for Advanced Hematologic Malignant Neoplasms

The frequency and clinical phenotypes of cardiotoxic events in chimeric antigen receptor (CAR) T-cell recipients remain poorly understood given that landmark approval trials typically exclude patients with high-risk cardiovascular profiles and data from nontrial settings are scarce. To summarize the prevalence of adverse cardiovascular events among adults receiving CAR T-cell therapies for advanced hematologic malignant neoplasms. MEDLINE, Embase, Cochrane Library, and Google Scholar were systematically searched from database inception until February 26, 2024. Observational studies were included if they comprised adult CAR T-cell recipients with advanced hematologic malignant neoplasms and if they systematically evaluated cardiovascular complications. Extraction of prespecified parameters related to the patient population, study design, and clinical events was performed at the study level by 2 independent reviewers in accordance with the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Meta-analysis of single proportions was conducted using random-effect models with Freeman-Tukey double arcsine transformations to calculate pooled prevalence estimates. Sensitivity analysis was performed using generalized linear mixed models with logit transformations. Ventricular and supraventricular arrhythmias, heart failure events, reduction in left ventricular ejection fraction, myocardial infarction, and cardiovascular and all-cause mortality. Thirteen studies comprising 1528 CAR T-cell recipients (median [IQR] age, 61 [58.7-63.0] years; 1016 males [66%]; 80% patients with lymphoma) were included. The median (IQR) duration of follow-up was 487 (294-530) days. On random-effects meta-analysis, we observed a pooled prevalence of 0.66% (95% CI, 0.00%-2.28%) for ventricular arrhythmia, 7.79% (95% CI, 4.87%-11.27%) for supraventricular arrhythmia, 8.68% (95% CI, 2.26%-17.97%) for left ventricular dysfunction, 3.87% (95% CI, 1.77%-6.62%) for heart failure events, 0.62% (95% CI, 0.02%-1.74%) for myocardial infarction, and 0.63% (95% CI, 0.13%-1.38%) for cardiovascular death. The pooled prevalence of all-cause mortality was 30.01% (95% CI, 19.49%-41.68%). Sensitivity analyses generated similar findings. This meta-analysis found a low prevalence of ventricular arrhythmia, myocardial infarction, and cardiovascular death among CAR T-cell recipients over a short-term to midterm follow-up. Left ventricular dysfunction and supraventricular arrhythmia were the most commonly reported cardiovascular complications, suggesting that cardiovascular surveillance strategies should focus on decreases in ejection fraction and supraventricular arrhythmia.

Directly Isolated Allogeneic Virus–Specific T Cells in Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a life-threatening viral infection with no approved antiviral treatment. To determine whether restoring the compromised immune system of patients with PML with directly isolated allogeneic virus-specific (DIAVIS) T cells is a promising therapeutic strategy, especially if other curative options are absent. A retrospective case series of patients with PML who were treated with DIAVIS T cells was conducted between March 2020 and February 2022. T cells were isolated from healthy donors within 24 hours and targeted against the BK polyomavirus. Patients with PML were treated monocentrically. Eligibility for treatment with DIAVIS T cells was assessed for patients with confirmed PML, and exclusion criteria included stable PML disease and previous treatment with natalizumab. Fresh DIAVIS T cells were administered with a maximum dose of 2 × 104 CD3+ cells/kg body weight. Remaining T cells were cryopreserved in divided doses and administered in additional treatments approximately 2 and 6 weeks later. Primary outcome measures were clinical response and survival of patients, compared with the outcomes of a historical reference group of PML cases receiving best supportive treatment (BST) and with recently published real-world data of patients with PML who were treated with immune checkpoint inhibition. The study cohort consisted of 28 patients (median [IQR] age, 60 [51-72] years; 20 male [71.4%]). Twenty-two patients (79%) treated with DIAVIS T cells showed response, resulting in significant clinical stabilization or improvement and a reduction in viral load. Six individuals (21%) were classified as nonresponders, deteriorated rapidly, and died, as did 2 other patients during a 12-month follow-up. Older age was the only predictor of a poor treatment response. Survival analysis revealed better 12-month survival rates (hazard ratio, 0.42; 95% CI, 0.24-0.73; P =.02) from diagnosis for patients treated with DIAVIS T cells (18 of 26 [69%]; 12-mo survival rate, 69%) compared with historical controls with BST (57 of 113 [50%]; 12-mo survival rate, including censored data, 45%). This case series of DIAVIS T-cell therapy in PML provides first class IV evidence suggesting efficacy to reduce mortality and improve functional outcome. Further prospective studies are required to confirm these results.

Chimeric antigen receptor-T-cell therapies going viral: latent and incidental viral infections.

Infections are the leading cause of non-relapse mortality following chimeric antigen receptor (CAR)-T-cell therapy, with viral infections being frequent both in the early and late phases post-infusion. We review the epidemiology of viral infections and discuss critical approaches to prevention and management strategies in this setting. Herpesviruses dominate the early period. herpes simplex virus and varicella zoster virus infections are rare due to widespread antiviral prophylaxis, but cytomegalovirus (CMV) reactivation is increasingly observed, particularly in high-risk groups including B cell maturation antigen (BCMA)-CAR-T-cell therapy recipients and patients receiving corticosteroids. While CMV end-organ disease is rare, CMV is associated with increased mortality, emphasizing the need to evaluate the broader impact of CMV on long-term hematological, infection, and survival outcomes. Human herpesvirus-6 (HHV-6) has also emerged as a concern, with its diagnosis complicated by overlapping symptoms with neurotoxicity, underscoring the importance of considering viral encephalitis in differential diagnoses. Respiratory viruses are the most common late infections with a higher incidence after BCMA CAR-T-cell therapy. Vaccination remains a critical preventive measure against respiratory viruses but may be less immunogenic following CAR-T-cell therapy. The optimal timing, type of vaccine, and dosing schedule require further investigation. A better understanding of viral epidemiology and preventive trials are needed to improve infection prevention practices and outcomes following CAR-T-cell therapies.

S100 as marker for immune effector cell-associated neurotoxicity syndrome.

Chimeric antigen receptor (CAR)-Tcell therapy is anew and successful treatment for otherwise refractory malignancies but despite the growing number of applications, this form of treatment is still associated with significant toxicity. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in particular are common and dangerous side effects. This report is about two patients who received CAR‑T cell therapy and subsequently developed ICANS. This was successfully treated. During CAR‑T cell therapy, ablood marker, S100, was monitored daily. It correlated with the occurrence and progression of ICANS.

Transient EZH2 suppression by Tazemetostat during in vitro expansion maintains T-cell stemness and improves adoptive T-cell therapy.

The histone methyltransferase enhancer of zeste homolog 2 (EZH2) plays important roles in T-cell differentiation, proliferation and function. Previous studies have demonstrated that genetic deletion of EZH2 in CD8+ or total T cells impairs their antiviral and antitumor activity, cytokine production and ability to expand upon rechallenge. Contrary to the detrimental role of deleting T cell-intrinsic EZH2, here we have demonstrated that transient inhibition of EZH2 in T cells prior to the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetostat, delayed their dysfunctional progression and preserved T-cell stemness and polyfunctionality but had no negative impact on cell proliferation. Tazemetostat induced T-cell epigenetic reprogramming and increased the expression of the self-renewal T-cell transcription factor TCF1 by reducing H3K27 methylation at its promoter preferentially in rapidly dividing T cells. In a murine melanoma model, T cells depleted of EZH2 induced poor tumor control, whereas adoptively transferred T cells pretreated with tazemetostat exhibited superior antitumor immunity, especially when used in combination with anti-PD-1 blockade. Collectively, these data highlight the potential of transient epigenetic reprogramming by EZH2 inhibition to enhance adoptive T-cell immunotherapy.

PD-1 blockade does not improve efficacy of EpCAM-directed CAR T-cell in lung cancer brain metastasis

BackgroundLung cancer brain metastasis has a devastating prognosis, necessitating innovative treatment strategies. While chimeric antigen receptor (CAR) T-cell show promise in hematologic malignancies, their efficacy in solid tumors, including brain metastasis, is limited by the immunosuppressive tumor environment. The PD-L1/PD-1 pathway inhibits CAR T-cell activity in the tumor microenvironment, presenting a potential target to enhance therapeutic efficacy. This study aims to evaluate the impact of anti-PD-1 antibodies on CAR T-cell in treating lung cancer brain metastasis.MethodsWe utilized a murine immunocompetent, syngeneic orthotopic cerebral metastasis model for repetitive intracerebral two-photon laser scanning microscopy, enabling in vivo characterization of red fluorescent tumor cells and CAR T-cell at a single-cell level over time. Red fluorescent EpCAM-transduced Lewis lung carcinoma cells (EpCAM/tdtLL/2 cells) were implanted intracranially. Following the formation of brain metastasis, EpCAM-directed CAR T-cell were injected into adjacent brain tissue, and animals received either anti-PD-1 or an isotype control.ResultsCompared to controls receiving T-cell lacking a CAR, mice receiving EpCAM-directed CAR T-cell showed higher intratumoral CAR T-cell densities in the beginning after intraparenchymal injection. This finding was accompanied with reduced tumor growth and translated into a survival benefit. Additional anti-PD-1 treatment, however, did not affect intratumoral CAR T-cell persistence nor tumor growth and thereby did not provide an additional therapeutic effect.ConclusionCAR T-cell therapy for brain malignancies appears promising. However, additional anti-PD-1 treatment did not enhance intratumoral CAR T-cell persistence or effector function, highlighting the need for novel strategies to improve CAR T-cell therapy in solid tumors.

Aggressive Lymphoma after CD19 CAR T-Cell Therapy

SummaryThe development of a fatal, clonal, autonomously proliferating CD4−CD8− chimeric antigen receptor (CAR)+ peripheral T-cell lymphoma (PTCL) occurred 1 month after a patient received treatment with tisagenlecleucel for relapsed primary central nervous system lymphoma. The PTCL had a clonal T-cell receptor rearrangement, which was already detectable in the apheresis product for CAR T-cell manufacturing and 7 months earlier for autologous transplantation. Somatic DNMT3A and TET2 mutations in CD34+ stem cells and their progeny were detected in the PTCL, in the apheresis specimen that was obtained for CAR T-cell production, and in the autotransplant. The PTCL harbored an additional somatic TET2 mutation, which was already detectable in the CAR T-cell apheresis product and the final CAR T-cell product at very low frequencies, providing evidence that clonal hematopoiesis had contributed to lymphomagenesis.

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.

EASIX-guided risk stratification for complications and outcome after CAR T-cell therapy with ide-cel in relapsed/refractory multiple myeloma

BackgroundChimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release...

Prognostic significance of fludeoxyglucose positron emission tomography delta radiomics following bridging therapy in patients with large B-cell lymphoma undergoing CAR T-cell therapy.

Bridging radiation therapy (bRT) is increasingly being utilized prior to chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL). It is unknown how the extent of cytoreduction during bRT impacts outcomes. We retrospectively reviewed patients with LBCL treated with bRT followed by CAR T-cell therapy. Metabolic tumor volume (MTV), maximum standardized uptake value (SUVmax), SUVmean, and total lesion glycolysis (TLG) were extracted from F18-fluorodeoxyglucose positron emission tomography (PET) scans acquired prior to bRT and between completion of bRT and CAR T-cell infusion. Delta radiomics based on changes of these values were then calculated. The association between delta radiomics and oncologic outcomes [progression-free survival (PFS), freedom from distant progression (FFDP), and local control (LC)] were then examined. Thirty-three sites across 23 patients with LBCL were irradiated. All metabolically active disease was treated in 10 patients. Following bRT, median overall decreases (including unirradiated sites) in MTV, SUVmax, SUVmean, and TLG were 22.2 cc (63.1%), 8.9 (36.8%), 3.4 (31.1%), and 297.9 cc (75.8%), respectively. Median decreases in MTV, SUVmax, SUVmean, and TLG in irradiated sites were 15.6 cc (91.1%), 17.0 (74.6%), 6.8 (55.3%), and 157.0 cc (94.6%), respectively. Median follow-up was 15.2 months. A decrease in SUVmax of at least 54% was associated with improved PFS (24-month PFS: 83.3% vs. 28.1%; p = 0.037) and FFDP (24-month FFDP: 100% vs. 62.4%; p < 0.001). A decrease in MTV of at least 90% was associated with improved FFDP (24-month FFDP: 100% vs. 62.4%; p < 0.001). LC was improved in sites with decreases in SUVmax of at least 71% (24-month LC: 100% vs. 72.7%; p < 0.001). Decreases of MTV by at least 90% (100% vs. 53.3%; p = 0.038) and TLG by at least 95% (100% vs. 56.3%; p = 0.067) were associated with an improved complete response rate. bRT led to substantial reductions in MTV, SUVmax, SUVmean, and TLG. The relative extent of these decreases correlated with improved outcomes after CAR T-cell infusion. Prospective cohorts should validate the value of interim PET following bRT for quantifying changes in disease burden and associated prognosis.

Revisiting T-cell adhesion molecules as potential targets for cancer immunotherapy: CD226 and CD2.

Cancer immunotherapy aims to initiate or amplify immune responses that eliminate cancer cells and create immune memory to prevent relapse. Immune checkpoint inhibitors (ICIs), which target coinhibitory receptors on immune effector cells, such as CTLA-4 and PD-(L)1, have made significant strides in cancer treatment. However, they still face challenges in achieving widespread and durable responses. The effectiveness of anticancer immunity, which is determined by the interplay of coinhibitory and costimulatory signals in tumor-infiltrating immune cells, highlights the potential of costimulatory receptors as key targets for immunotherapy. This review explores our current understanding of the functions of CD2 and CD226, placing a special emphasis on their potential as novel agonist targets for cancer immunotherapy. CD2 and CD226, which are present mainly on T and NK cells, serve important functions in cell adhesion and recognition. These molecules are now recognized for their costimulatory benefits, particularly in the context of overcoming T-cell exhaustion and boosting antitumor responses. The importance of CD226, especially in anti-TIGIT therapy, along with the CD2‒CD58 axis in overcoming resistance to ICI or chimeric antigen receptor (CAR) T-cell therapies provides valuable insights into advancing beyond the current barriers of cancer immunotherapy, underscoring their promise as targets for novel agonist therapy.

Successful generation of fully human, second generation, anti-CD19 CAR T cells for clinical use in patients with diverse autoimmune disorders

BackgroundB-cell targeting chimeric antigen receptor (CAR) T-cell therapies, which lead to profound B-cell depletion, have been well-established in hematology-oncology. This deep B-cell depletion mechanism has prompted the exploration of their use in B-cell driven autoimmune diseases. We herein report on the manufacturing of KYV-101, a fully human anti-CD19 CAR T-cell therapy, derived from patients who were treated across a spectrum of autoimmune diseases. MethodsKYV-101 was manufactured from peripheral blood-derived mononuclear cells of 20 patients across 7 autoimmune disease types (neurological autoimmune diseases, n=13; rheumatological diseases, n=7). Patients ranged from 18–75 years of age. Duration of disease ranged from <1–23 years since diagnosis. Patients were heavily pretreated, and most were refractory to prior immunosuppressive treatments. Apheresis was collected across 9 sites, cryopreserved, and shipped to the manufacturing facility. Healthy donor apheresis samples were collected for manufacturing comparison. Manufacturing was performed using the CliniMACS Prodigy system. Cells were enriched for CD4+/CD8+ T cells, transduced with a 3rd generation lentiviral vector encoding the CAR, expanded in vitro, and harvested. Percent cell viability, T-cell purity, cellular expansion, and transduction efficiency were assessed. Activity was assessed using cytokine release assays for KYV-101 CAR T cells co-cultured with different CD19+/– target cell lines. ResultsKYV-101 was successfully manufactured for 100% of patients. Transduced cell populations were highly viable, with expansion ranging from 11–66 fold at Day 8, and were comparable across disease types. Healthy donor-derived controls displayed similar expansion ranges. High CAR expression and transduction rates were observed, ranging between 37–84% with low variation in transgene copy number (2 to 4 per cell). Cell viability of the final KYV-101 drug product ranged from 87–97%. KYV-101 displayed robust CD19-dependent and effector dose-related release of the pro-inflammatory cytokine IFN-γ. ConclusionsKYV-101 manufacturing yielded a CAR T-cell product with high viability and consistent composition and functionality, regardless of disease indication, pre-treatment, and heterogeneity of the incoming material. Cryopreservation of the apheresis and final drug product enabled widespread distribution. These results support the robustness of the manufacturing process for the fully human KYV-101 anti-CD19 CAR T-cell therapy drug product for patients across diverse autoimmune disease types.

Unlocking Apoptotic Pathways: Overcoming Tumor Resistance in CAR-T-Cell Therapy.

Chimeric antigen receptor (CAR)-T-cell therapy has transformed cancer treatment, leading to remarkable clinical outcomes. However, resistance continues to be a major obstacle, significantly limiting its efficacy in numerous patients. This review critically examines the challenges associated with CAR-T-cell therapy, with a particular focus on the role of apoptotic pathways in overcoming resistance. We explore various strategies to sensitize tumor cells to CAR-T-cell-mediated apoptosis, including the use of combination therapies with BH3 mimetics, Mcl-1 inhibitors, IAP inhibitors, and HDAC inhibitors. These agents inhibit anti-apoptotic proteins and activate intrinsic mitochondrial pathways, enhancing the susceptibility of tumor cells to apoptosis. Moreover, targeting the extrinsic pathway can increase the expression of death receptors on tumor cells, further promoting their apoptosis. The review also discusses the development of novel CAR constructs that enhance anti-apoptotic protein expression, such as Bcl-2, which may counteract CAR-T cell exhaustion and improve antitumor efficacy. We assess the impact of the tumor microenvironment (TME) on CAR-T cell function and propose dual-targeting CAR-T cells to simultaneously address both myeloid-derived suppressor cells (MDSCs) and tumor cells. Furthermore, we explore the potential of combining agents like PPAR inhibitors to activate the cGAS-STING pathway, thereby improving CAR-T cell infiltration into the tumor. This review highlights that enhancing tumor cell sensitivity to apoptosis and increasing CAR-T cell cytotoxicity through apoptotic pathways could significantly improve therapeutic outcomes. Targeting apoptotic proteins, particularly those involved in the intrinsic mitochondrial pathway, constitutes a novel approach to overcoming resistance. The insights presented herein lay a robust foundation for future research and clinical applications aimed at optimizing CAR-T cell therapies.

Spatiotemporal dynamics of tumor - CAR T-cell interaction following local administration in solid cancers.

The success of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic malignancies has generated widespread interest in translating this technology to solid cancers. However, issues like tumor infiltration, the immunosuppressive tumor microenvironment, and tumor heterogeneity limit its efficacy in the solid tumor setting. Recent experimental and clinical studies propose local administration directly into the tumor or at the tumor site to increase CAR T-cell infiltration and improve treatment outcomes. Characteristics of the types of solid tumors that may be the most receptive to this treatment approach remain unclear. In this work, we develop a spatiotemporal model for CAR T-cell treatment of solid tumors, and use numerical simulations to compare the effect of introducing CAR T cells via intratumoral injection versus intracavitary administration in diverse cancer types. We demonstrate that the model can recapitulate tumor and CAR T-cell data from imaging studies of local administration of CAR T cells in mouse models. Our results suggest that locally administered CAR T cells will be most successful against slowly proliferating, highly diffusive tumors, which have the lowest average tumor cell density. These findings affirm the clinical observation that CAR T cells will not perform equally across different types of solid tumors, and suggest that measuring tumor density may be helpful when considering the feasibility of CAR T-cell therapy and planning dosages for a particular patient. We additionally find that local delivery of CAR T cells can result in deep tumor responses, provided that the initial CAR T-cell dose does not contain a significant fraction of exhausted cells.

Solid cancer-directed CAR T cell therapy that attacks both tumor and immunosuppressive cells via targeting PD-L1

Chimeric antigen receptor (CAR) T-cell therapy has encountered limited success in solid tumors. The lack of dependable antigens and the immunosuppressive tumor microenvironment (TME) are major challenges. Within the TME, tumor cells along with immunosuppressive cells employ an immune-evasion mechanism that upregulates programmed death ligand 1 (PD-L1) to deactivate effector T cells; this makes PD-L1 a reliable, universal target for solid tumors. We developed a novel PD-L1 CAR (MC9999) using our humanized anti-PD-L1 monoclonal antibody, designed to simultaneously target tumor and immunosuppressive cells. The antigen-specific antitumor effects of MC9999 CAR T-cells were observed consistently across four solid tumor models: breast cancer, lung cancer, melanoma, and glioblastoma multiforme (GBM). Notably, intravenous administration of MC9999 CAR T-cells eradicated intracranially established LN229 GBM tumors, suggesting penetration of the blood-brain barrier. The proof-of-concept data demonstrate the cytolytic effect of MC9999 CAR T-cells against immunosuppressive cells, including microglia HMC3 cells and M2 macrophages. Furthermore, MC9999 CAR T-cells elicited cytotoxicity against primary tumor-associated macrophages within GBM tumors. The concept of targeting both tumor and immunosuppressive cells with MC9999 was further validated using CAR T-cells derived from cancer patients. These findings establish MC9999 as a foundation for the development of effective CAR T-cell therapies against solid tumors.

A Systematic Review on the Epidemiology and Treatment Options of Multiple Myeloma in Asia

Multiple myeloma (MM) accounts for almost 15% of all neoplastic malignancies around the globe. This systematic review intends to analyse data on the treatment and management of MM in selected regions in Asia to identify and prioritize areas that need attention. A comprehensive review of original articles, published in English from 2005 to 2022, derived from the PubMed/MEDLINE database was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. There were 98 studies from select regions of Asia (China, India, Taiwan, Hong Kong, and Singapore) on newly diagnosed MM and relapsed/refractory MM. This review evaluated the trends in disease outcomes with the gradual shift in treatment regimens from doublet to triplet. Additionally, this review also explored autologous stem cell transplant outcome and anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy in MM patients. This is the first systematic review attempting to collect data on the utility and comparison of innovative agents and modifications in treatment regimens in the context of the Asian population. This review established that the body of evidence for the management of MM was generally of poor quality and there is a need for more versatile studies in the region. Novel and innovative drug regimens may help in combating the illness but consorted efforts by researchers, industry partners, policymakers, and the government are key factors in the long-term survival of MM patients. In the current systematic review, the authors have tried to give a comprehensive account of the available treatments, trends in MM management and prognosis for MM in Asia.