CAR T cells in combination with anti-CD47 failed to promote tumor clearance due to systemic macrophage-mediated depletion of CAR T cells, which was so pronounced that anti-CD47 could function as a CAR T cell safety switch. A CD47 variant (47E) was designed to evade antibody blockade while maintaining function as a “don’t eat me” signal. 47E T cells resisted depletion and induced myeloid-activating/attracting genes in intratumoral T cells, which promoted phagocytic macrophage infiltration. 47E T cells + anti-CD47 promoted significant tumor control and survival across multiple solid and liquid models incorporating CAR or TCR T cells.
Contributed by Morgan Janes
ABSTRACT: Adoptively transferred T cells and agents designed to block the CD47-SIRP_ axis are promising cancer therapeutics that activate distinct arms of the immune system(1,2). Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47(E)), which engages SIRP_ and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47(E) are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile(3), the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.
Author Info: (1) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco,
Author Info: (1) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (2) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (3) Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA. (4) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA. (5) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Masters in Translational Research and Applied Medicine Program, Stanford University School of Medicine, Stanford, CA, USA. (6) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (7) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (8) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (9) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (10) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (11) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (12) British Columbia Cancer Agency, Vancouver, British Columbia, Canada. (13) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (14) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA. (15) Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. Princess Mxima Center for Pediatric Oncology, Utrecht, The Netherlands. (16) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA. (17) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Department of Bioengineering, Stanford University, Stanford, CA, USA. (18) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA. (19) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Program in Biophysics, Stanford University, Stanford, CA, USA. Medical Scientist Training Program, Stanford University, Stanford, CA, USA. (20) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (21) Medical Scientist Training Program, Stanford University, Stanford, CA, USA. Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA. Neurosciences Program, Stanford University, Stanford, CA, USA. (22) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (23) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (24) Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (25) Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (26) Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA. Medical Scientist Training Program, Stanford University, Stanford, CA, USA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (27) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (28) Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA. (29) Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. (30) Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. (31) British Columbia Cancer Agency, Vancouver, British Columbia, Canada. (32) Medical Scientist Training Program, Stanford University, Stanford, CA, USA. Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA. Neurosciences Program, Stanford University, Stanford, CA, USA. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (33) Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (34) Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA. (35) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (36) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (37) Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA. Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA. Department of Bioengineering, Stanford University, Stanford, CA, USA. Department of Chemical Engineering, Stanford University, Stanford, CA, USA. (38) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. cmackall@stanford.edu. Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu. Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
