Clinical Trials of Cellular Therapies in Solid Tumors

Abstract

In the past years cancer treatments have drastically changed, mainly due to the development of immune checkpoint inhibitors capable of immune modulation in vivo, thus providing major clinical benefit in a number of malignancies. Simultaneously, considerable technical refinements have opened new prospects for the development of immune cell-based medicinal products and unprecedented success with chimeric antigen receptor (CAR)-T cells targeting B-cell hematologic malignancies has been obtained. However, T cell therapies introduced and performed in the field of solid tumors have produced so far only limited responses in selected patient populations. This standstill is attributable to the difficulty in identifying target antigens which are homogeneously expressed by all tumor cells while absent from normal tissues, and the limited T cell persistence and proliferation in a hostile tumor microenvironment that favors immune escape. Replicating the results observed in hematology is a major scientific challenge in solid tumors, and ongoing translational and clinical research is focused on obtaining insight into the mechanisms of tumor recognition and evasion, and how to improve the efficacy of cellular therapies, also combining them with immune checkpoint inhibitors or other agents targeting either the cancer cell or the tumor environment. This paper provides an overview of current adaptive T cell therapy approaches in solid tumors, the research performed to increase their efficacy and safety, and results from ongoing clinical trials.

Keywords: ACT; CAR-T; adoptive T cell therapy; immunotherapy; solid tumors.

Figure 1

Multiple cell types available for adoptive cell therapies (on the left) and tumor mechanism to avoid T cell response (on the right). Tumor evasion includes loss of tumor neoantigens, upregulation of checkpoint ligands, immunosuppressive soluble tumor factors, immunosuppressive cells, such as T-reg, macrophages, myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblast (CAFs).