Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity

Leyuan Ma; Alexander Hostetler; Duncan M Morgan; Laura Maiorino; Ina Sulkaj; Charles A Whittaker; Alexandra Neeser; Ivan Susin Pires; Parisa Yousefpour; Justin Gregory; Kashif Qureshi; Jonathan Dye; Wuhbet Abraham; Heikyung Suh; Na Li; J Christopher Love; Darrell J Irvine

doi:10.1016/j.cell.2023.06.002

Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity

Cell. 2023 Jul 20;186(15):3148-3165.e20. doi: 10.1016/j.cell.2023.06.002. Epub 2023 Jul 5.

Authors

Leyuan Ma¹, Alexander Hostetler², Duncan M Morgan³, Laura Maiorino², Ina Sulkaj², Charles A Whittaker², Alexandra Neeser⁴, Ivan Susin Pires², Parisa Yousefpour², Justin Gregory², Kashif Qureshi², Jonathan Dye², Wuhbet Abraham², Heikyung Suh², Na Li², J Christopher Love⁵, Darrell J Irvine⁶

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: leyuan.ma@pennmedicine.upenn.edu.
² David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
³ David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Chemical Engineering, MIT, Cambridge, MA, USA.
⁴ Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Chemical Engineering, MIT, Cambridge, MA, USA; Ragon Institute of Massachusetts General Hospital, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Materials Science and Engineering, MIT, Cambridge, MA 02139, USA; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA; Ragon Institute of Massachusetts General Hospital, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: djirvine@mit.edu.

Abstract

Chimeric antigen receptor (CAR) T cell therapy effectively treats human cancer, but the loss of the antigen recognized by the CAR poses a major obstacle. We found that in vivo vaccine boosting of CAR T cells triggers the engagement of the endogenous immune system to circumvent antigen-negative tumor escape. Vaccine-boosted CAR T promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited the priming of endogenous anti-tumor T cells. This process was accompanied by shifts in CAR T metabolism toward oxidative phosphorylation (OXPHOS) and was critically dependent on CAR-T-derived IFN-γ. Antigen spreading (AS) induced by vaccine-boosted CAR T enabled a proportion of complete responses even when the initial tumor was 50% CAR antigen negative, and heterogeneous tumor control was further enhanced by the genetic amplification of CAR T IFN-γ expression. Thus, CAR-T-cell-derived IFN-γ plays a critical role in promoting AS, and vaccine boosting provides a clinically translatable strategy to drive such responses against solid tumors.

Keywords: CAR T; IFN-γ; antigen loss; antigen spreading; antigenic heterogeneity; cancer; chimeric antigen receptor T cell; immunotherapy; solid tumor; tumor heterogeneity; vaccine.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Cancer Vaccines*
Humans
Immunotherapy, Adoptive
Neoplasms* / therapy
Receptors, Antigen, T-Cell / metabolism
Receptors, Chimeric Antigen*
T-Lymphocytes

Substances

Receptors, Chimeric Antigen
Cancer Vaccines
Receptors, Antigen, T-Cell

Abstract

Publication types

MeSH terms

Substances

Grants and funding