2024 Year End Overview: Developments in CAR T-Cell Therapy

MERIT’s LIN Chengyu, MD, Associate Medical Director, China, and Gene Kim, PharmD, Associate Director of Medical Affairs & Innovation, Oncology provide insights into early phase CAR-T studies in solid tumors.

Introduction: What is CAR-T?

The National Cancer Institute describes CAR T-cell therapy as a type of treatment in which a patient’s T cells are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient’s blood. Then the gene for a special receptor that binds to a certain protein on the patient’s cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion.

Compared to conventional small molecule drugs and antibodies, CAR T-cell therapy, although expensive, has an advantage of single dose delivery, rather than continuous weekly or daily drug administration. Additionally, due to the unique nature of cell therapy, CAR T-cell therapy requires a process of cell collection, preparation, and infusion for each individual patient. This poses significant challenges for biopharmaceuticals in terms of manufacturing processes, quality control, and production timelines. Several CAR T-cell therapy products were granted marketing approval in multiple regions for certain blood cancers. Meanwhile, there are over a thousand clinical trials exploring CAR T-cell therapy in different solid tumors.¹

FDA and CAR T-Cell Therapies in the News

In early November 2024, the Food and Drug Administration (FDA) approved Autolus Inc.’s CAR T-cell therapy obecabtagene autoleucel (Aucatzyl) for the treatment of relapsed or refractory B-cell precursor Acute Lymphoblastic Leukemia (ALL). Aucatzyl is a CD19-directed genetically modified autologous T cell immunotherapy. Gilead’s Tecartus and Novartis’ Kymriah are also approved in ALL, but Aucatzyl may gain an advantage as the only CAR T that doesn’t come with an FDA requirement for a Risk Evaluation Mitigation Strategy (REMS) program.²

Earlier in October, the FDA and CAR-T-cell therapies were also in the news as the agency lifted its clinical holds on three of CARsgen U.S.’s clinical trials of zevor-cel, satri-cel, and CT071. The holds had been placed due to CMC concerns after an inspection of the company’s manufacturing facility.³ Earlier in the summer, the FDA also lifted a hold on Gilead’s CAR T-cell clinical trial, which had been paused due to the death of a patient. The FDA lifted the hold after signing off on an updated trial protocol and agreeing to an expanded range of bridging therapies.⁴

As recent news indicates, there is continuing industry interest in these therapies. Indeed, there have been several important developments in the field in 2024, particularly in the area of solid tumors. The articles highlighted below offer some details on early phase CAR T clinical trials reported at ASCO and ESMO 2024.

Logic-Gated CAR T-Cell Therapies

CAR T-cell therapies for solid tumors face challenges due to the lack of tumor-specific targets, leading to toxicities when the therapy fails to distinguish cancer from normal cells. A2B530 is a new CAR T-cell therapy that uses a logic-gated approach to target CEA on tumor cells while avoiding normal cells by using a blocking receptor that binds HLA-A*02.

The EVEREST-1 study (NCT05736731) is a phase 1/2 trial evaluating the safety and efficacy of A2B530 in patients with CEA-expressing cancers. Patients are pre-screened through the BASECAMP-1 study (NCT04981119) to identify those with HLA LOH. Eligible patients undergo leukapheresis, and their T cells are manufactured for the trial. The study aims to determine the recommended phase 2 dose (RP2D) and assess the overall response rate. As of January 29, 2024, 8 patients had been enrolled, and all received A2B530 infusions. Dose escalation was ongoing at the time of publication.⁵

Armored CAR T-Cell Therapies in Solid Tumors

Glypican 3 (GPC3) is highly expressed in several cancers, including hepatocellular carcinoma (HCC). TAK-102 is a GPC3-targeted CAR T-cell therapy enhanced (armored) with IL-7 and CCL19 to improve CAR T-cell persistence and overcome the immunosuppressive tumor environment. This Phase 1 dose-escalation study evaluated TAK-102 in patients with GPC3-expressing solid tumors who were refractory to standard treatments. TAK-102 was administered in three dose levels after lymphodepleting chemotherapy. The study aimed to assess safety, dose-limiting toxicity, recommended phase 2 dose, and antitumor activity. Eleven patients received TAK-102. Five achieved stable disease, with the greatest tumor reduction being 26.4%. No dose-limiting toxicities or neurotoxicity were observed. Cytokine release syndrome occurred in six patients but was manageable. Tumor marker AFP levels decreased or stabilized in some patients. TAK-102 exposure improved from dose level 1 to 2, with a slight decrease from level 2 to 3. Dose-dependency was observed in cytokine levels, indicating increased activity. TAK-102 showed a manageable safety profile and early signs of antitumor activity in heavily treated patients with advanced Hepatocellular Carcinoma (HCC).⁶

CAR T-Cell Therapies in HCC

Another CAR T-cell therapy targeting GPC3, C-CAR031, is also designed to treat advanced HCC. This first-in-human, open-label trial uses a dose-escalation design. Patients with advanced HCC who failed at least one systemic treatment received a single infusion of C-CAR031. The primary endpoints are safety and tolerability, with secondary endpoints including pharmacokinetics and preliminary efficacy. As of January 5, 2024, 24 patients received C-CAR031 at four dose levels. Most patients had advanced HCC with metastasis and had undergone multiple prior treatments. No dose-limiting toxicities or ICANS were observed. CRS occurred in 91.7% of patients, mostly mild. Common severe adverse events included lymphocytopenia, neutropenia, and thrombocytopenia. Tumor reductions were seen in 90.9% of patients, with a disease control rate of 90.9% and an objective response rate of 50%. C-CAR031 demonstrated a manageable safety profile and promising anti-tumor activity in heavily treated advanced HCC patients.⁷

CAR T-Cell Therapies in Glioblastoma (GBM)

CAR T-cell therapy in solid tumors like glioblastomas faces challenges due to tumor heterogeneity and immunosuppressive environments, but some Phase I studies show promising early results.

CARv3-TEAM-E T-cells

The INCIPIENT study investigated the safety and efficacy of CARv3-TEAM-E T-cells in patients with glioblastoma. This study provides a promising proof of concept for targeting glioblastoma with engineered T-cells.

Previous studies with CART-EGFRvIII showed on-target effects but no radiographic responses due to tumor cells expressing wild-type EGFR and infiltration by regulatory T-cells. CARv3-TEAM-E T-cells were engineered to target EGFRvIII and secrete antibodies against wild-type EGFR, which is commonly expressed in glioblastoma but not in normal brain tissue. A phase I clinical trial was conducted with patients having recurrent or newly diagnosed EGFRvIII-positive glioblastoma. Participants received a single infusion of CARv3-TEAM-E T-cells and were monitored for safety. Three patients were enrolled from March to July 2023. No dose-limiting toxicities were observed. Notable side effects included grade 3 encephalopathy and fatigue in two participants. Radiographic responses were seen shortly after infusion, with one participant showing durable regression. However, tumor progression was noted in two participants, linked to limited persistence of the T-cells. The study demonstrated that CARv3-TEAM-E T-cells can target multiple antigens and are safe. Despite some antitumor activity, further research is needed to enhance the durability of the treatment, possibly through preconditioning or additional infusions.⁸

CART-EGFR-IL13Rα2 cells

In a study published on March 13, 2024, in Nature Medicine, Dr. Stephan J. Bagley and colleagues reported on a phase I trial involving six patients with recurrent glioblastoma treated with bivalent CAR T-cells targeting EGFR and IL13Rα2.

The primary endpoints were safety and determining the maximum tolerated dose. Secondary endpoints included manufacturing failures and objective radiographic response (ORR). All six patients had progressive, multifocal glioblastoma. They were divided into two dose levels: 1×10^7 cells (dose level 1) and 2.5×10^7 cells (dose level 2). Early-onset neurotoxicity was observed in all patients, managed with high-dose dexamethasone and anti-IL1R. One patient in dose level 2 experienced a dose-limiting toxicity (DLT) of grade 3 anorexia, muscle weakness, and fatigue. Reductions in tumor enhancement and size were seen in all patients, but none met the criteria for ORR. High levels of CAR T-cells and cytokine release were detected in cerebrospinal fluid. The study demonstrated preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells, with an encouraging early efficacy signal that needs further confirmation with more patients and longer follow-up. This study provides initial evidence that these engineered T-cells could be a viable treatment for recurrent glioblastoma, though more research is needed.⁹

Conclusion

In conclusion, early phase clinical trials in CAR T-cell therapy are paving the way for innovative cancer treatments. The encouraging preliminary results from these trials highlight the potential of CAR T-cell therapy to revolutionize the treatment of cancer, offering new hope to patients with limited options. Continued research and clinical trials will be crucial in refining these therapies and ensuring their safety and efficacy for broader clinical use.