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49 First-in-Human Assessment of Feasibility and Safety of Multiplexed Genetic Engineering of Autologous T Cells Expressing NY-ESO -1 TCR and CRISPR/Cas9 Gene Edited to Eliminate Endogenous TCR and PD-1 (NYCE T cells) in Advanced Multiple Myeloma (MM) and Sarcoma

Program: Oral and Poster Abstracts
Type: Oral
Session: 801. Gene Therapy and Transfer: Advancing CAR T Cells: New Biology and Therapeutic Applications
Hematology Disease Topics & Pathways:
Adult, Biological, multiple myeloma, Diseases, bioengineering, Therapies, CAR-Ts, checkpoint inhibitors, Technology and Procedures, cell expansion, gene therapy, Study Population, immunotherapy, Plasma Cell Disorders, Clinically relevant, gene editing, Lymphoid Malignancies
Saturday, December 7, 2019: 7:30 AM
W414AB, Level 4 (Orange County Convention Center)

Edward A. Stadtmauer, MD, FACP1, Adam D. Cohen, MD1, Kristy Weber, MD2*, Simon F Lacey, PhD3, Vanessa E. Gonzalez3*, J. Joseph Melenhorst, PhD3, Joseph A Fraietta, PhD3*, Gabriela Plesa, MD3*, Joanne Shea3*, Tina Matlawski, RN3*, Amanda Cervini, RN3*, Patricia Mangan, CRNP1*, Avery Gaymon3*, Stephanie Desjardins3*, Eric Lancaster, MD4*, January Salas-Mckee3*, Megan M. Suhoski, PhD3*, Andrew Fesnak, MD3*, Matthew O'Rourke3*, Anne Lamontagne3*, Don L. Siegel, MD, PhD5, Regina M Young, PhD3*, Anne Chew, PhD3*, Christopher L Nobles, PhD6*, Frederic D. Bushman, PhD7*, Howard Y. Chang, MD, PhD8*, Ansuman T. Satpathy, MD, PhD8*, Yangbing Zhao, PhD, MD3*, Wei-Ting Hwang, PhD3*, Elizabeth O. Hexner, MD, MS1 and Carl H June, MD3

1University of Pennsylvania Abramson Cancer Center, Philadelphia, PA
2Department of Orthopaedic Surgery, University of Pennsylvania Abramson Cancer Center, Philadelphia, PA
3Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
4Department of Neurology, University of Pennsylvania, Philadelphia, PA
5Center for Cellular Immunotherapies, Univ. of PA Med. Ctr., Philadelphia, PA
6Department of Microbiology, University of Pennsylvania, Philadelphia, PA
7Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
8Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University, Palo Alto, CA

Background: Autologous T cells genetically modified with a lentiviral vector to express affinity-enhanced T cell receptors (TCR) or chimeric antigen receptors have shown great promise for the treatment of cancer. NY-ESO-1 is a cancer testis antigen with little normal tissue expression but with aberrant expression in MM, sarcomas, and melanomas. An HLA-A201 restricted TCR recognizing the NY-ESO-1/LAGE-1 157-165 epitope (SLLMWITQC) kills NY-ESO positive cell lines and has been used to treat 25 patients with MM after ASCT with expansion, persistence, antigen-directed functionality and long-term safety and antitumor activity (Nat Med 2015, Blood Adv 2019). We hypothesized removal of the genes encoding the endogenous TCR, TCRα (TRAC) and TCRβ (TRBC), would enhance NY-ESO TCR expression and reduce TCR mispairing and with removal of PD-1 (PDCD1) would enhance activity and persistence. We previously demonstrated CRISPR/Cas9 and TCRα, TCRβ and PDCD1 targeting gRNAs could be successfully introduced via electroporation in preclinical models to disrupt gene expression (Clin Cancer Res 2017). We therefore began a phase 1 pilot clinical trial for pts with advanced MM and sarcoma of NY-ESO-1 TCR-expressing T cells with CRISPR/Cas9 TCRα, TCRβ and PDCD1 edited genes to assess safety, feasibility and activity (NCT03399448).

Methods: Adults with HLA-A*0201 and expressing NY-ESO-1 and/or LAGE-1 antigen with advanced MM, synovial sarcoma, and myxoid/round cell liposarcoma (MRCL) with adequate performance and organ function and, for MM relapsed or refractory to at least 3 prior regimens and, for MRCL, proven metastatic disease or surgically inoperable local recurrence, were enrolled. Autologous T cells were transfected with Cas9 protein complexed with single guide RNAs against TRAC, TRBC and PDCD1 and subsequently transduced to express NY-ESO-1-specific TCR at the University of Pennsylvania. Frequency of NYCE T cells in final product was measured by flow cytometric dextramer analysis. Once cells were successfully manufactured and released, pts received fludarabine 30mg/m2 and cyclophosphamide 300mg/m2 daily on day -4,-3,-2. On Day 0 pts received a single infusion of thawed NYCE T cells as an out-patient. Pts were monitored closely for the first 28 days, monthly till 6 mo and then followed every 3 mo for adverse events, antitumor response and survival, NYCE T cell expansion, persistence, trafficking, phenotype and function, and immunogenicity. An assessment after accrual of the first 3 subjects in this ongoing trial was planned and is reported here.

Results: 3 pts, 2 with MM and 1 with MRCL, have received NYCE T cells. Pt 1 is a 67 y/o F with IgG kappa MM with lytic bone lesions, and a +17q after 8 lines of therapy including 3 ASCTs, lenalidomide, pomalidomide, bortezomib, carfilzomib, daratumumab, and panobinostat. Pt 2 is a 65 y/o M with a recurrent MRCL manifested by abdominal and pelvic involvement after neo-adjuvant doxorubicin, multiple resections and radiation treatments with progression at time of enrollment. Pt 3 is a 62 y/o F with kappa light chain MM with lytic bone lesions and plasmacytomas and a +1q after 7 lines of therapy including lenalidomide, pomalidomide, bortezomib, carfilzomib, daratumumab, 2 ASCTs and an immunoconjugate . Manufacturing for these pts resulted in satisfactory products with 89.4 to 96% viability, transduction efficiency by qPCR of 0.04 to 0.2 copies/cell , residual Cas9 concentration 0 to 0.37 ng/ml, dextramer 0.4 to 1.8% NY-ESO-1 expression. TRAC, TRBC, and PDCD1 disruption efficiency was 44.3 to 49.4, 3.61 to 15.7 and 15.6 to 20.2% respectively. Pts tolerated treatment well without neurotoxicity or CRS. By day +60 pt 1 progressed by IMWG. Pt 2 received 1 U PRBC. By day +90 he remained with stable disease by serial CT scans. Pt 3 is too early to evaluate. Serial qPCR for copies of lentiviral transcripts in peripheral blood and tumor biopsies for pts 1+2 showed in vivo expansion, stable persistence and tumor targeting (Figure).

Conclusion: Early results of a phase 1 trial of NYCE T cells infused in 3 pts with advanced MM and MRCL show safety and feasibility and viable, expanding, and persisting CRISPR/Cas9 gene edited T cells that trafficked to tumor. The persistence of the NYCE T cells suggests that immunogenicity from multiplexed gene-editing using Cas9 is minimal under these conditions. Further characterization of phenotype and function of these cells and clinical outcomes will be presented.

Disclosures: Stadtmauer: Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding. Cohen: Poseida Therapeutics, Inc.: Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Abramson Cancer Center/University of Pennsylvania received research support for this clinical trial, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Lacey: Novartis: Patents & Royalties: Patents related to CAR T cell biomarkers; Tmunity: Research Funding; Novartis: Research Funding. Melenhorst: Incyte: Research Funding; Novartis: Research Funding, Speakers Bureau; Parker Institute for Cancer Immunotherapy: Research Funding; Genentech: Speakers Bureau; Stand Up to Cancer: Research Funding; IASO Biotherapeutics, Co: Consultancy; Simcere of America, Inc: Consultancy; Shanghai Unicar Therapy, Co: Consultancy; Colorado Clinical and Translational Sciences Institute: Membership on an entity's Board of Directors or advisory committees; National Institutes of Health: Research Funding. Fraietta: Tmunity: Research Funding; Cabaletta: Research Funding; LEK Consulting: Consultancy. Mangan: amgen: Speakers Bureau; takeda: Speakers Bureau; celgene: Speakers Bureau; janssen: Speakers Bureau. Lancaster: novartis: Research Funding. Suhoski: novartis: Research Funding. Fesnak: Novartis: Research Funding. Young: novartis: Research Funding. Chew: tmunity: Other: Scientific Founder, Research Funding; novartis: Research Funding. Zhao: Tmunity: Membership on an entity's Board of Directors or advisory committees, Research Funding; novartis: Research Funding. Hwang: Novartis: Research Funding; Tmunity: Research Funding. Hexner: novartis: Research Funding. June: Novartis: Research Funding; Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties.

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