Clinical Investigations of CAR-T Cell Therapy for Solid Tumors

Abstract

Cell therapy is a distinguished targeted immunotherapy with great potential to treat solid tumors in the new era of cancer treatment. Cell therapy products include genetically engineered cell products and non-genetically engineered cell products. Several recent cell therapies, especially chimeric antigen receptor (CAR)-T cell therapies, have been approved as novel treatment strategies for cancer. Many clinical trials on cell therapies, in the form of cell therapy alone or in combination with other treatments, in solid tumors, have been conducted or ongoing. However, there are still challenges since adverse events and the limited efficacy of cell therapies have also been observed. Here, we concisely summarize the clinical milestones of the conducted and ongoing clinical trials of cell therapy, introduce the evolution of CARs, discuss the challenges and limitations of these therapeutic modalities taking CAR-T as the main focus, and analyze the disparities in the regulatory policies in different countries.

Keywords: cellular immunotherapy; chimeric antigen receptors; genetically engineered; solid tumors; tumor microenvironment.

Figure 1

Timeline of important events for cell therapy in solid tumors. After the first adoptive cellular immunotherapy, LAK opened the gate of cell therapy in 1985. Cell therapy has rapidly evolved in the last 10 years with a consistent appearance of novel types. The transformation from the non-genetic engineering model to genetic engineering-based products is the most important direction.

Figure 2

Trend of clinical trials on cell therapy worldwide and in China. (A) Newly initiated active clinical trials on cell therapy have increased especially after 2014, and the dominating type is converting from vaccine to CAR/TCR-T. (B) Newly initiated active clinical trials in China continue to increase since 2015, and the dominating type is CAR/TCR. (C) Newly initiated active clinical trials increase both in and outside of China (since 2015).

Figure 3

Chimeric antigen receptors and main challenges of treating solid tumors. Evolution of CAR from the first generation to the fourth generation. First-generation CARs. Second-generation CARs embody an additional intracellular signaling domain to the first-generation receptor configuration and provide a co-stimulatory signal. Third-generation receptors incorporate two co-stimulatory domains with the T-cell-activating signaling domain. Fourth-generation CARs or TRUCKS (T cells redirected for universal cytokine killing) carry vectors that encode a CAR and a CAR-responsive promoter as well as respond to the successful signaling of CAR by the transgenic production of cytokines such as IL-12. Upon accumulated knowledge of solid tumors and their surrounding environment, more effective CAR therapeutic products may be generated. CAR, chimeric antigen receptors.