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Dr. Rapoport- Adoptive Transfer of Gene-Modified T-Cells Engineered to Express High-Affinity TCRs for Cancer-Testis Antigens (CTAs) NY-ESO-1 or Lage-1, in MM Patients Post Auto-SCT
Aaron Rapoport, MD
University of Maryland
Baltimore, MD
Program: Oral and Poster Abstracts
Type: Oral
Session: 731. Clinical Allogeneic and Autologous Transplantation - Results: Strategies to Prevent or Treat Relapse After Transplantation
Monday, December 10, 2012: 11:15 AM
B312-B313a, Level 3, Building B (Georgia World Congress Center)

Aaron P. Rapoport, MD1, Edward A. Stadtmauer, MD2*, Dan T. Vogl, MD, MSCE3, Brendan M Weiss, MD3, Gwendolyn K. Binder-Scholl, PhD4*, Joanna E. Brewer, PhD5*, Alan D. Bennett, PhD5*, Andrew B. Gerry, PhD5*, Nick J. Pumphrey, PhD5*, Dominic P. Smethurst, MD5*, Helen K. Tayton-Martin, PhD5*, Ribeiro C. Lilliam, MBe4*, Elizabeth Veloso, JD, BSN3*, Zhaohui Zheng, MA6*, Ashraf Z. Badros, MD1, Saul Yanovich, MD1, Gorgun Akpek, MD, MHS1*, Holly McConville, RN, BSN3*, Naseem Kerr, MPH3*, Sunita Philip, MPH1*, Kelly-Marie Betts, MS1*, Sandra Westphal1*, Michael Kalos, PhD3, Bruce L. Levine, PhD6*, Bent K. Jakobsen, PhD5* and Carl H. June, MD2,6

1Greenebaum Cancer Center, University of Maryland, Baltimore, MD
2Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
3Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
4Adaptimmune LLC, Philadelphia, PA
5Adaptimmune Ltd, Abingdon, United Kingdom
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA

BackgroundDespite recent therapeutic advances, multiple myeloma (MM) remains primarily an incurable cancer. Patients experiencing rapid recovery of T cells post auto-SCT may have improved outcomes, and spontaneous cellular responses to tumor can occur, suggesting immune mediated control of tumor is possible.  We and others have investigated therapeutic cancer vaccines that have shown promise in pilot studies.  However, vaccine efficacy may be limited by thymic selection which restricts the repertoire of T cell receptors (TCRs) to low affinity TCRs that cannot recognize the reduced level of antigen present on most tumor cells. We hypothesized that incorporation of affinity-enhanced tumor antigen specific TCRs into autologous T cells would overcome this limitation. 

Methods:We report interim results of a Phase II clinical trial (NCT01352286) to evaluate the safety and activity of autologous T cells genetically engineered to express an HLA-A201 restricted, affinity-enhanced TCR targeting an epitope shared by the NY-ESO-1 and LAGE-1 tumor antigens (gene engineered cells, or GEC).  Inclusion criteria include: 1) eligibility for auto-SCT, 2) PS of 0-2, 3) high risk MM or relapse after prior therapy (prior allo-SCT excluded), 4) HLA-A201 positive, and 5) NY-ESO-1 and/or LAGE-1 positive tumor.  GEC are manufactured from monocyte and T regulatory cell depleted apheresis, followed by lentivector gene transfer and T cell expansion by bead-based artificial antigen presenting cells.  GEC are administered four days after high dose melphalan and two days following auto-SCT, at a dose range of 1-10 billion cells.  Patients are evaluated for MM responses in accordance with the IMWG criteria at 6 weeks, and 3 and 6 months post infusion.  At 3 months, patients start lenalidomide maintenance.  The initial 6 patient phase is complete and a 20 patient extension phase is ongoing.

Results:19 patients have been enrolled, 12 have been infused, 3 are pending infusion, and 4 were taken off study prior to infusion due to disease progression.  The average TCR transfer efficiency was 31.9% (range 18.2%-45%).  6, 4, and 1 patients have reached the 6 month, 3 month, and 6 week post infusion MM assessment time points, respectively.  All treated patients are alive.  3/11 (27%) and 7/11 (64%) patients have a stringent CR or best response of VGPR or better, respectively; 3/11 (27%) have stable or partial responses, and 1/11 (9%) had progressive disease.  In patients with VGPR, oligoclonal banding was common, marrow showed no expansion of clonal plasma cells, and all had normalized light chain ratios, suggesting at most minimal residual disease.  These results are encouraging, especially considering that 3/11 patients had prior ASCT and 8/11 had adverse cytogenetics.  GEC infusions have been well tolerated.  The majority of adverse events are related to the high dose melphalan.  Several patients had a transient skin rash with lymphocytosis and others had a diarrheal syndrome that occurred later than expected for melphalan-induced mucositis.  In all cases GI toxicity has been self-limited or treatable with a short dose of corticosteroids.  Possibly related SAEs were cytopenias such as neutropenia and thrombocytopenia, and GI and metabolism disorders such as diarrhea, colitis, hyponatremia and hypomagnesemia.  GEC have been detected for up to 1 year at 1% in the circulation and bone marrow.  Detailed correlative analysis is reported elsewhere in this meeting (Kalos, M. et al).

Summary: This is the first test of GEC in the MM setting.  Infusion of GEC administered post auto-SCT is safe, well tolerated, and leads to high response rate in a high risk myeloma population.  Phase II accrual continues and a study evaluating GEC outside of auto-SCT is planned.

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