Assessing the Future of Solid Tumor Immunotherapy

Abstract

With the advent of cancer immunotherapy, there has been a major improvement in patient's quality of life and survival. The growth of cancer immunotherapy has dramatically changed our understanding of the basics of cancer biology and has altered the standards of care (surgery, radiotherapy, and chemotherapy) for patients. Cancer immunotherapy has generated significant excitement with the success of chimeric antigen receptor (CAR) T cell therapy in particular. Clinical results using CAR-T for hematological malignancies have led to the approval of four CD19-targeted and one B-cell maturation antigen (BCMA)-targeted cell therapy products by the US Food and Drug Administration (FDA). Also, immune checkpoint inhibitors such as antibodies against Programmed Cell Death-1 (PD-1), Programmed Cell Death Ligand-1 (PD-L1), and Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) have shown promising therapeutic outcomes and long-lasting clinical effect in several tumor types and patients who are refractory to other treatments. Despite these promising results, the success of cancer immunotherapy in solid tumors has been limited due to several barriers, which include immunosuppressive tumor microenvironment (TME), inefficient trafficking, and heterogeneity of tumor antigens. This is further compounded by the high intra-tumoral pressure of solid tumors, which presents an additional challenge to successfully delivering treatments to solid tumors. In this review, we will outline and propose specific approaches that may overcome these immunological and physical barriers to improve the outcomes in solid tumor patients receiving immunotherapies.

Keywords: CAR-NK; CAR-T; On-target-off-tumor-toxicity; adoptive cell therapy; cytokine release syndrome; immune checkpoint inhibitors; myeloid derived suppressor cells; single chain variable fragment (scFv); tumor microenvironment.

Figure 1

Adoptive cell transfer from patient tumor or blood. (1) Production begins with isolation of peripheral blood mononuclear cells (PBMC) from leukapheresis or tumor is excised and multiple individual cultures are isolated and (2) plated separately followed by (3) selection and activation of T cells. (4) T cells then undergo genetic modification for generating CAR-T cells or tumor cultures are assayed for specific tumor recognition. (5) Cells are expanded in presence of interleukins and when desired dose cell numbers are achieved, expanded cells are harvested and dose is formulated. (6) QC tests are performed to ensure that drug meets release criteria and is then fused into patients with or without conditioning lymphodepleting chemotherapy (6).

Figure 2

Four generations of CAR-T cells. First generation CARs comprise of single chain variable fragment (scFv) antibody (orange) fused to transmembrane domain (purple) to TCR signaling component of CD3ζ (green) at the cytoplasmic tail. Second generation CARs have a CD28 co-stimulatory signaling domain (red) which enhances proliferation and cytotoxicity. Third generation CARs contain an additional co-stimulatory domain, 4-1BB (blue) to the second generation CARs which enhances proliferation, minimizes T cell exhaustion and improves CAR-T cells persistence. Fourth generation CARs also called “T cell directed for universal cytokine-mediated killing” (TRUCKs) are engineered to secrete cytokines (gray) to attract immune cells (NK and macrophages).