Abstract and Introduction
Abstract
In recent years, treatment with chimeric antigen receptor (CAR) T-cells has revolutionized the outcomes of patients with relapsed or refractory hematological malignancies with long-term remissions in >30% of patients. Similarly, the introduction of immune checkpoint inhibitor therapy changed the therapeutic landscape for several solid malignancies also leading to impressive long-term remission in patients. However, so far CAR T-cell therapy in solid tumors has shown low response rates and especially a lack of long-term remissions. This review focuses on the latest clinical advances and discusses promising results seen with CAR T-cells exploring new target antigens. We then review relevant challenges limiting long-term responses with CAR T-cell therapy in solid tumors like CAR T-cell persistence and target antigen expression. In addition, there is an increasing understanding on T-cell function and dysfunction within the immunosuppressive tumor microenvironment. This comprises of inhibitory cytokines and checkpoint molecules limiting the killing capacity of CAR T-cells. Finally, we will discuss how this deeper knowledge can be used to develop CAR T-cell therapies overcoming these inhibitory factors and results in CAR T-cell products with higher efficacy and safety. These technological developments will hopefully lead to enhanced clinical activity and improved solid tumor patient outcomes in the near future.
Introduction
In the past decade, chimeric antigen receptor (CAR) T-cell therapy emerged as novel and highly innovative therapeutic modality for hematological malignancies, with durable complete response rates of >30% in heavily pre-treated patients.[1] CAR T-cell therapy is nowadays considered to be standard of care for patients with refractory or relapsed hematological cancers, including B-cell acute lymphoblastic leukemia (B-ALL), large B-cell lymphoma (LBCL), primary mediastinal B cell lymphoma (PMBCL), follicular lymphoma, mantel cell lymphoma and multiple myeloma.[2–4] CAR T-cell therapy aims at the generation of a robust anti-tumor immune response.[5] Most commonly, autologous T-cells are isolated and genetically engineered, via retro- or lentiviral transduction or more recently by clustered regularly interspaced short palindromic repeats (CRISPR) gene editing, which results in the expression of a synthetic CAR that redirects T-cell specificity and reactivity towards the selected membrane-bound tumor-associated target antigen.[6] Hereto, the CAR contains several functional domains including an antigen recognition domain (antibody-derived single-chain variable fragment), a hinge domain, a transmembrane domain, a costimulatory domain and a T-cell activation domain.[5] In this way, the CAR integrates primary TCR-driven activation with secondary stimulation provided by co-stimulatory molecules. After in vitro expansion, the CAR T-cell product is infused into the patient, which is most frequently preceded by chemotherapy to increase the plasma levels of lymphoproliferative cytokines [e.g., interleukin (IL)-7, IL-15, IL-21] and to limit suppressive effects of immunomodulatory cells, such as regulatory T-cells. CAR T-cells proliferate in vivo after administration into the patient and long-term persistence has been described. A single injection of these cells would theoretically be sufficient to induce long-term anti-tumor efficacy in patients with hematological malignancies. The cytokine release syndrome (CRS) and immune effector cell associated neurologic syndrome (ICANS) are well-known toxicities of immune effector cells therapy, as recently reviewed.[7] These toxicities are in general well manageable with supportive care and immunosuppressive agents, e.g., the IL-6 receptor antagonist tocilizumab or corticosteroids.[7]
In contrast, the results of CAR T-cell therapy in solid oncology have been less encouraging so far. Important factors that hamper the success of this cellular immunotherapy in solid tumors include the selection of an appropriate tumor-associated target antigen, the complex hostile and immunosuppressive tumor microenvironment (TME) and the limited persistence of the CAR T-cells.[8] However, the field changes at rapid pace and many innovative strategies are currently being developed to improve CAR T-cell efficacy for solid tumors. This review focusses on the emerging role of CAR T-cell therapy in solid tumor oncology by discussing promising clinical studies as well as the challenges that need to be overcome.
Chin Clin Oncol. 2023;12(2):19 © 2023 AME Publishing Company
