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CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

By Poornima Ramkumar, Anthony B Abarientos, Ruilin Tian, Meghan Seyler, Jaime T Leong, Merissa Chen, Priya Choudhry, Torsten Hechler, Nina Shah, Sandy W. Wong, Thomas G. Martin, Jeffrey L. Wolf, Kole T. Roybal, Andreas Pahl, Jack Taunton, Arun P. Wiita, Martin Kampmann

Posted 07 Nov 2019
bioRxiv DOI: 10.1101/833707 (published DOI: 10.1182/bloodadvances.2019001346)

Cancer cells commonly develop resistance to immunotherapy by loss of antigen expression. Combinatorial treatments that increase levels of the target antigen on the surface of cancer cells have the potential to restore efficacy to immunotherapy. Here, we use our CRISPR interference and CRISPR activation-based functional genomics platform to systematically identify pathways controlling cell-surface expression of the multiple myeloma immunotherapy antigen - B cell maturation antigen, BCMA. We discovered that pharmacological inhibition of HDAC7 and the Sec61 complex increased cell-surface BCMA, including in primary patient cells. Importantly, pharmacological Sec61 inhibition enhanced the anti-myeloma efficacy of a BCMA-targeted antibody-drug conjugate. A CRISPR interference CAR-T coculture screen enabled us to identify both antigen-dependent and -independent mechanisms controlling response of myeloma cells to BCMA-targeted CAR-T cells. Thus, our study demonstrates the potential of CRISPR screens to uncover mechanisms controlling response of cancer cells to immunotherapy and to suggest potential combination therapies. ### Competing Interest Statement M.K. has filed a patent application related to CRISPRi and CRISPRa screening (PCT/US15/ 40449) and serves on the Scientific Advisory Board of Engine Biosciences. A.P. and T.H. are employed at Heidelberg Pharma (A.P.) and Heidelberg Pharma Research GmbH (T.H.) and are working on the development of Amatoxin based ADCs (including HDP-101). Heidelberg Pharma holds patents concerning the conjugation of Amatoxins to antibodies. K.T.R is a cofounder and stockholder in Arsenal Biosciences. K.T.R was a founding scientist/consultant and stockholder in Cell Design Labs now a Gilead Company. K.T.R holds stock in Gilead. J.T. is a cofounder and shareholder of Global Blood Therapeutics, Principia Biopharma, Kezar Life Sciences, and Cedilla Therapeutics. J.T. is listed as an inventor on a provisional patent application describing PS3061. A.P.W. is a member of the scientific advisory board and equity holder in Protocol Intelligence, LLC, and Indapta Therapeutics, LLC.

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