Combination Immunotherapy after ASCT for Multiple Myeloma Using MAGE-A3/Poly-ICLC Immunizations Followed by Adoptive Transfer of Vaccine-Primed and Costimulated Autologous T Cells

Abstract

Purpose Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-primed and costimulated autologous T cells. Experimental Design In a phase II clinical trial (NCT01245673), we evaluated the safety and activity of ex vivo expanded autologous T cells primed in vivo using a MAGE-A3 multipeptide vaccine (compound GL-0817) combined with Poly-ICLC (Hiltonol), granulocyte macrophage colony-stimulating factor (GM-CSF) ± montanide. Twenty-seven patients with active and/or high-risk myeloma received autografts followed by anti-CD3/anti-CD28–costimulated autologous T cells, accompanied by MAGE-A3 peptide immunizations before T-cell collection and five times after ASCT. Immune responses to the vaccine were evaluated by cytokine production (all patients), dextramer binding to CD8+ T cells, and ELISA performed serially after transplant. Results T-cell infusions were well tolerated, whereas vaccine injection site reactions occurred in >90% of patients. Two of nine patients who received montanide developed sterile abscesses; however, this did not occur in the 18 patients who did not receive montanide. Dextramer staining demonstrated MAGE-A3–specific CD8 T cells in 7 of 8 evaluable HLA-A2+ patients (88%), whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients (76%). Antibody responses developed in 7 of 9 patients (78%) who received montanide and only weakly in 2 of 18 patients (11%) who did not. The 2-year overall survival was 74% [95% confidence interval (CI), 54%–100%] and 2-year event-free survival was 56% (95% CI, 37%–85%). Conclusions A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF–primed MAGE-A3 vaccine.

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

“…64 Dextramer staining demonstrated MAGE-A3-specific CD8 T cells in 7 of 8 evaluable HLA-A2+ patients, whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients. Further studies are needed to determine the clinical impact of this approach.…”

The immunotherapy era of myeloma: monoclonal antibodies, vaccines, and adoptive T-cell therapies

“…They found an 88% dextramer positivity in HLA-A2 patients but failed to prove a statistically significant correlation between vaccine specificity and clinical responses. 65 GM-CSF-based cellular vaccines. The ability to prime immune responses toward a greater number of tumor-associated antigens maximizes the likelihood of achieving broader antimyeloma coverage.…”

Personalized approaches to active immunotherapy in cancer

“…This therapy lead to one complete remission and two stable disease in the six stage IV melanoma patients enrolled in the trial [180]. Similar approach, for enhancing vaccines efficiency, may be provided by adoptive transfer of vaccine-primed ex-vivo expanded T cells [181,182]. We have sought to enhance personalized DCs vaccine efficacy by lymphodepletion followed by adoptive transfer of ex-vivo CD3/CD28-costimulated, vaccine-primed T cells.…”