Incorporation of Immune Checkpoint Blockade into Chimeric Antigen Receptor T Cells (CAR-Ts): Combination or Built-In CAR-T

Dok Hyun Yoon; Mark J Osborn; Jakub Tolar; Chong Jai Kim

doi:10.3390/ijms19020340

Incorporation of Immune Checkpoint Blockade into Chimeric Antigen Receptor T Cells (CAR-Ts): Combination or Built-In CAR-T

Int J Mol Sci. 2018 Jan 24;19(2):340. doi: 10.3390/ijms19020340.

Authors

Dok Hyun Yoon^{1 2 3 4}, Mark J Osborn^{5 6 7 8 9}, Jakub Tolar^{10 11 12 13 14}, Chong Jai Kim¹⁵

Affiliations

¹ Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea. dhyoon@amc.seoul.kr.
² Asan-Minnesota Institute for Innovating Transplantation, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea. dhyoon@amc.seoul.kr.
³ Asan-Minnesota Institute for Innovating Transplantation, University of Minnesota, Minneapolis, MN 55455, USA. dhyoon@amc.seoul.kr.
⁴ Department of Pediatrics, University of Minnesota Medical School, Division of Blood and Marrow Transplantation, Minneapolis, MN 55455, USA. dhyoon@amc.seoul.kr.
⁵ Asan-Minnesota Institute for Innovating Transplantation, University of Minnesota, Minneapolis, MN 55455, USA. osbor026@umn.edu.
⁶ Department of Pediatrics, University of Minnesota Medical School, Division of Blood and Marrow Transplantation, Minneapolis, MN 55455, USA. osbor026@umn.edu.
⁷ Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. osbor026@umn.edu.
⁸ Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA. osbor026@umn.edu.
⁹ Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA. osbor026@umn.edu.
¹⁰ Asan-Minnesota Institute for Innovating Transplantation, University of Minnesota, Minneapolis, MN 55455, USA. tolar003@umn.edu.
¹¹ Department of Pediatrics, University of Minnesota Medical School, Division of Blood and Marrow Transplantation, Minneapolis, MN 55455, USA. tolar003@umn.edu.
¹² Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. tolar003@umn.edu.
¹³ Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA. tolar003@umn.edu.
¹⁴ Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA. tolar003@umn.edu.
¹⁵ Asan-Minnesota Institute for Innovating Transplantation, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea. ckim@amc.seoul.kr.

Abstract

Chimeric antigen receptor (CAR) T cell therapy represents the first U.S. Food and Drug Administration approved gene therapy and these engineered cells function with unprecedented efficacy in the treatment of refractory CD19 positive hematologic malignancies. CAR translation to solid tumors is also being actively investigated; however, efficacy to date has been variable due to tumor-evolved mechanisms that inhibit local immune cell activity. To bolster the potency of CAR-T cells, modulation of the immunosuppressive tumor microenvironment with immune-checkpoint blockade is a promising strategy. The impact of this approach on hematological malignancies is in its infancy, and in this review we discuss CAR-T cells and their synergy with immune-checkpoint blockade.

Keywords: CRISPR/Cas9; PD-1; adoptive T cell therapy; cancer immunotherapy; chimeric antigen receptors; gene editing; gene therapy; immune-checkpoint.

Publication types

Review

MeSH terms

Animals
Antineoplastic Agents, Immunological / pharmacology*
Antineoplastic Agents, Immunological / therapeutic use
Combined Modality Therapy
Gene Editing
Genetic Therapy
Hematologic Neoplasms / immunology
Hematologic Neoplasms / therapy
Humans
Immunotherapy, Adoptive*
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Receptors, Antigen, T-Cell / genetics
Receptors, Antigen, T-Cell / metabolism*
Recombinant Fusion Proteins*
T-Lymphocytes / immunology*
T-Lymphocytes / metabolism*
Tumor Microenvironment / drug effects
Tumor Microenvironment / immunology

Substances

Antineoplastic Agents, Immunological
PDCD1 protein, human
Programmed Cell Death 1 Receptor
Receptors, Antigen, T-Cell
Recombinant Fusion Proteins