Next-Generation CAR T-cell Therapies

Abstract

Summary: CD19- and B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T cells have enabled unprecedented responses in a subset of refractory patients with B-cell and plasma cell malignancies, leading to their approval by the FDA for the treatment of leukemia, lymphoma, and myeloma. These “living drugs” can become part of a synthetic immune system, persisting at least a decade in some patients. However, despite this tremendous impact, significant unmet treatment needs remain for patients with hematologic malignancies and solid cancers. In this perspective, we highlight recent innovations that advance the field toward production of a more potent and universal cellular immunotherapy of the future. Next-generation CAR T cells will incorporate advances in gene engineering and synthetic biology to enhance functionality and persistence, and reduce treatment-associated toxicities. The combination of autologous CAR T cells with various allogeneic cell treatment strategies designed to target the immunosuppressive tumor microenvironment will broaden the impact of future CAR T-cell therapies.

First-in-human phase I study of CLL-1 CAR-T cells in adults with relapsed/refractory acute myeloid leukemia

“…To the Editor, R/R AML patients have poor long-term survival [1,2]. T cells expressing CAR have been recognized as a promising approach for hematological malignancies [3], but the effects of CAR-T cell therapy in R/R AML are limited and need to be improved [4,5]. Human C-type lectin-like molecule 1 (CLL-1) is expressed on malignant cells in more than 90% of AML patients, but is underexpressed in normal hematopoietic stem cells [6].…”

Overcoming tumor resistance mechanisms in CAR-NK cell therapy

“…Despite the multiple advantages, CAR-NK therapy still has to confront additional shortcomings that provoke resistance and impact on its efficacy, as seen in CAR-T cells ( 38 ). Herein, we will discuss these mechanisms, especially focusing on the CAR-NK dysfunctionalities that lead to immune surveillance evasion by hematologic tumors.…”

Harnessing natural killer cells to develop next‐generation cellular immunotherapy

“… 1 Cellular immunotherapy, as most prominently exemplified by the chimeric antigen receptor T (CAR‐T) cell therapy, harnesses the body's immune system to specifically engage and eliminate cancer cells. 1 , 2 , 3 , 4 The goal of cancer immunotherapies is to enhance the patient's immune response to detect and clear cancerous cells, especially cells with accumulated mutations that allow them to evade the host immune system. To achieve this, immune cells are engineered to express specific receptors, such as chimeric antigen receptors (CARs).…”

“…For instance, among the six FDA‐approved CAR‐T cell therapies, four products (Kymriah, Yescarta, Tecartus, and Breyanzi) target the CD19 antigen overexpressed in leukemia or lymphoma cells to treat acute lymphoblastic leukemia (ALL) and relapsed or refractory diffuse B‐cell lymphoma (DLBCL), whereas the remaining two products (Abecma and Carvykti) target the B‐cell major antigen (BCMA) to treat multiple myeloma. 1 , 2 , 5 , 6 , 7 , 8 , 9 , 10 …”

“… 1 CAR‐T cells have shown remarkable efficacy in patients with relapsed or refractory hematological malignancies. 1 , 2 , 3 , 4 However, their wide application is limited by several non‐negligible side effects and/or inherent drawbacks, including graft‐versus‐host‐disease (GvHD), cytokine release syndrome (CRS), potential “on‐target off‐tumor” cytotoxicity, and failure of efficient infiltration into solid tumors due to the immunosuppressive TME. 11 , 12 CAR‐expressing NK (designated “CAR‐NK”) cells, nevertheless, are capable of overcoming some of these roadblocks because of their advantages over CAR‐T cells in killing malignant cells with fewer adverse side effects after transplantation.…”