[ Visit Client Website ]

Before you can access ASH's online program, you must agree to the following:
  • Abstracts submitted to the ASH Annual Meeting are considered embargoed from the time of submission.
  • The media, companies and institutions issuing press releases, and others are required to abide by the embargo policies governing the Society’s annual meeting. Read ASH’s embargo policy for more information.
-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session .

755 Prolonged T Cell Persistence, Homing to Marrow and Selective Targeting of Antigen Positive Tumor in Multiple Myeloma Patients Following Adoptive Transfer of T Cells Genetically Engineered to Express an Affinity-Enhanced T Cell Receptor Against the Cancer Testis Antigens NY-ESO-1 and Lage-1

Program: Oral and Poster Abstracts
Type: Oral
Session: 801. Gene Therapy and Transfer I
Monday, December 10, 2012: 5:30 PM
C208-C210, Level 2, Building C (Georgia World Congress Center)

Michael Kalos, PhD1,2,3, Aaron P. Rapoport, MD4, Edward A. Stadtmauer, MD2, Dan T. Vogl, MD2, Brendan M Weiss, MD2, Gwendolyn K. Binder-Scholl, PhD5*, Dominic P. Smethurst, MD6*, Irina Kulikovskaya1,3*, Minnal Gupta1,3*, Timothy L Macatee1,3*, Jeffrey M Finklestein1,3*, Joanna E. Brewer, PhD6*, Alan D. Bennett, PhD6*, Andrew B. Gerry, PhD6*, Nick J. Pumphrey, PhD6*, Helen K. Tayton-Martin, PhD6*, Elizabeth Veloso, JD, BSN2*, Zhaohui Zheng, MA7*, Ashraf Z. Badros, MD8, Saul Yanovich, MD8, Gorgun Akpek, MD, MHS8*, Holly McConville, RN, BSN2*, Sunita Philip8*, Bruce L. Levine, PhD9*, Bent K. Jakobsen, PhD6* and Carl H. June, MD7,10

1Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
2Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
3Translational and Correlative Studies Laboratory, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
4Greenebaum Cancer Center, University of Maryland, Baltimore, MD
5Adaptimmune LLC, Philadelphia, PA
6Adaptimmune Ltd, Abingdon, United Kingdom
7Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
8Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD
9Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
10Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA

Background: Adoptive transfer of T cells genetically engineered to express affinity-enhanced T cell receptors (TcRs) specific for self-antigens is one approach to generate potent anti-tumor immunity, and this approach is being evaluated in a number of clinical trials. Although persistence of engineered T cells is positively correlated with response rates, a recurring observation to-date has been poor T cell persistence beyond the initial treatment window. We have recently initiated a Phase II clinical trial (NCT01352286) in patients with recurrent multiple myeloma (MM), to evaluate the safety and activity of autologous T cells genetically engineered to express an HLA-A201 restricted, affinity-enhanced TCR that targets an epitope shared by the NY-ESO-1 and LAGE-1 cancer testis antigens commonly expressed by MM. Clinical study details and outcomes are reported elsewhere in this meeting (Rapoport, A, Stadtmauer, E. et al.).  Here we report the in vivo expansion, bioactivity, trafficking, durable persistence, and anti-tumor activity of TcR modified cells in this trial.  

Methods: Subjects received high-dose melphalan, infusion of autologous hematopoietic stem cells on day 0, and infusion of gene engineered cells (GEC) on day +2. Persistence of GEC was assessed by quantitative ABI-Taqman based PCR and a qualified assay that detects the lentivirus backbone sequence. Surface expression of the introduced affinity-enhanced TcR α/β receptor was detected by multiparametric flow cytometry and TcR-specific dextramerTMreagents. NY-ESO-1 and LAGE-1 antigen expression in marrow samples was assessed by quantitative ABI-taqman based PCR and inventoried primer/probe sets.

Results: As of August 2012, we have screened marrow from 46 patients for NY-ESO- and LAGE-1 expression. Of these, 29 (63%) and 17 (37%) expressed LAGE-1 and NY-ESO-1, respectively by PCR.  LAGE-1 co-expression was observed in all cases with NY-ESO-1.  To date 12 patients have been infused with GEC. Robust engraftment was observed, with peak levels of gene-marked cells in peripheral blood and marrow ranging from 1 x 102-1 x 103 cells/µL and peak levels detected within the first 21 days post infusion. By day +100 the absolute number of GEC showed patient-specific and variable contraction, with a subset of patients maintaining GEC at 1 x 102-1 x 103 cells/µL, and a second subset where GEC contracted to 1 x 101-1 x 102cells/µL. Trafficking to and persistence of GEC  in marrow was observed. At both early (up to day +30) and, in a subset of patients, late timepoints (post day+42), circulating CD3+ T cells could be detected with surface expression of the affinity enhanced TcR. Engineered cells are detected in all patients at their latest timepoint by Q-PCR. To date we see no evidence for TCR mispairing with endogenous TCR.

Tumor-antigen and tumor-specific targeting by GEC was evaluated using Q-PCR and quantifying transcript levels of NY-ESO-1, LAGE-1, and CD138 (as a plasma cell marker) in marrow biopsies at enrollment, and days +42, +100, and +180.  In the initial cohort of 5 patients, selective reappearance of CD138 transcript is observed in 4 cases (2 sCR, 1 VGPR, 1 PR), with non-detectable or very weak expression of LAGE-1/NY-ESO-1 transcripts, suggesting specific targeting of tumor cells that express LAGE-1/NY-ESO-1. In the fifth patient, who has progressive disease and low engineered cell persistence, CD138 and LAGE-1/NY-ESO-1 transcripts are both present above pre-treatment levels. A second infusion was recently given to this patient.

Summary: Our studies show for the first time that adoptive transfer of affinity-enhanced TCR engineered T cells in MM patients results in prolonged T cell persistence, homing to marrow, and anti-tumor activity.

Disclosures: Binder-Scholl: Adaptimmune : Employment. Smethurst: Adaptimmune Ltd: Employment. Brewer: Adaptimmune Ltd: Employment. Bennett: Adaptimmune Ltd: Employment. Gerry: Adaptimmune Ltd: Employment. Pumphrey: Adaptimmune Ltd: Employment. Tayton-Martin: Adaptimmune Ltd: Employment. Levine: TxCell: Consultancy, Membership on an entity’s Board of Directors or advisory committees; University of Pennsylvania: financial interest due to intellectual property and patents in the field of cell and gene therapy. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight, financial interest due to intellectual property and patents in the field of cell and gene therapy. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight Patents & Royalties. Jakobsen: Adaptimmune Ltc: Employment. June: Novartis: entitled to receive royalties from patents licensed to Novartis, entitled to receive royalties from patents licensed to Novartis Patents & Royalties, Research Funding.

*signifies non-member of ASH