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812 Development of BCMA-targeted immunotherapy using vaccine-induced antigen-specific memory CD8+ T cells for treating patients with multiple myeloma
  1. Jooeun Bae,
  2. Derin Keskin,
  3. Yueyi Huang,
  4. Sean Rowell,
  5. Sarah Nikiforow,
  6. Gerry MacDonald,
  7. Jerome Ritz,
  8. Nikhil Munshi and
  9. Kenneth Anderson
  1. Dana Farber Cancer Institute, Boston, MA, USA


Background Multiple myeloma (MM) is a largely incurable cancer of the plasma cells. Despite remarkable recent advances in treatment using novel therapeutics, MM remains incurable. Previously, we reported a vaccination strategy that induced antigen-specific memory CD8+ T lymphocytes (CTL) against XBP1 (X-box binding protein 1), CD138 (Syndecan-1) and CS1 (SLAMF7), which are highly expressed in MM cells. Clinical trials on patients with smoldering MM have proven this multi-peptide vaccine’s safety and immunogenicity, and larger clinical trials are ongoing. We further developed a translational research strategy to combine vaccination with the ex vivo expansion and infusion of vaccine-induced antigen-specific memory T cells. As a first step, we focused on targeting the B cell maturation antigen (BCMA), as it is specifically and highly expressed on the MM cells, and developed a protocol to efficiently isolate and expand BCMA-specific memory CTL ex vivo.

Methods In conjunction with our proposed immunogenic heteroclitic BCMA peptide-based vaccine, we have developed a protocol to efficiently isolate and expand the antigen-specific memory CD8+ CTL ex vivo as a supplemental immunotherapy against MM.

Results We developed a feasible and efficient method to secure antigen-specific T cells following the induction of MM-specific CTL using immunogenic heteroclitic BCMA72-80 (YLMFLLRKI) peptide. The resulting CD8+ CTL show specific upregulation of various costimulatory molecules including CD28, 4-1BB, CD40L and OX40. Among the different conditions we evaluated, anti-CD3/CD28 (clinical grade) stimulation produced the greatest expansion of BCMA-specific CTL within 2 weeks and specifically induced the proliferation of antigen-specific central memory CTL (47% with anti-CD3/CD28 treatment vs. 6% without anti-CD3/CD28). To further enhance the efficacy of the final cell product, functionally active BCMA-specific IFN-g+ CTL were sorted and expanded with anti-CD3/CD28, IL-2 (200 units/ml) and IL-15 (10 ng/ml). Under the conditions, we found a significant and continuous expansion (day 3: 2-fold, day 14: 22-fold, day 21: 55-fold) of BCMA-specific CTL with high Th1 cytokine (IL-2, TNF-a) production and anti-tumor activity (CD107a upregulation) against MM, which were both the BCMA epitope-specific and HLA-A2-restricted.

Conclusions BCMA-specific CD8+ CTL can be effectively expanded using clinical grade anti-CD3/CD28 and IL-2/IL-15 to yield MM-specific memory CTL with robust poly-functional anti-tumor activities. These results provide the framework for combining BCMA-peptide vaccination and the specific cellular therapy using the vaccine-induced IFN-g+ memory T cells to further enhance anti-MM immunity and improve MM patient outcome.

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