Autologous Lymphocyte Infusion Supports Tumor Antigen Vaccine–Induced Immunity in Autologous Stem Cell Transplant for Multiple Myeloma

Abstract

Autologous stem cell transplant (autoSCT), the standard consolidation therapy for multiple myeloma, improves disease-free survival, but is not curative. This could be an ideal setting for immunologic therapy. However, the immune milieu is impaired after autoSCT. We hypothesized that autologous lymphocyte infusion would restore immune competence, allowing immunotherapies such as cancer vaccines to elicit tumor antigen-specific immunity in the setting of autoSCT. In this pilot study (NCT01380145), we investigated safety, immunologic, and clinical outcomes of autologous lymphocyte infusion combined with peri-autoSCT immunotherapy with recombinant MAGE-A3 (a multiple myelomaassociated antigen) and adjuvant. Thirteen patients with multiple myeloma undergoing autoSCT were enrolled. Autologous lymphocyte infusion and MAGE vaccination were well tolerated. Combination immunotherapy resulted in high-titer humoral immunity and robust, antigen-specific CD4 þ T-cell responses in all subjects, and the responses persisted at least one year post-autoSCT. CD4 þ T cells were polyfunctional and Th1-biased. CD8 þ T-cell responses were elicited in 3 of 13 subjects. These cells recognized naturally processed MAGE-A3 antigen. Median progression-free survival was 27 months, and median overall survival was not reached, suggesting no differences from standard-of-care. In 4 of 8 subjects tested, MAGE-A protein expression was not detected by IHC in multiple myeloma cells at relapse, suggesting therapy-induced immunologic selection against antigen-expressing clones. These results demonstrated that autologous lymphocyte infusion augmentation of autoSCT confers a favorable milieu for immunotherapies such as tumor vaccines. This strategy does not require ex vivo manipulation of autologous lymphocyte products and is an applicable platform for further investigation into combination immunotherapies to treat multiple myeloma.

How to Train Your T Cells: Overcoming Immune Dysfunction in Multiple Myeloma

“…Targeted antigen approaches include protein/peptide-based vac-cines that introduce tumor-associated antigens (TAA) to recruit native DCs for antigen processing/presentation and subsequent multiple myeloma-specific effector cell expansion (25). In the peritransplantation setting, studies have explored vaccines targeting MAGE-A3, hTERT, or survivin in conjunction with vaccine-primed autologous lymphocyte infusion (27)(28)(29). In SMM, a multipeptide vaccine targeting XBP1, CD138, and SLAMF7/CS1 (PVX-410) demonstrated singleagent immunogenicity that was enhanced with lenalidomide (30).…”

Emerging agents and regimens for multiple myeloma

“…It has been speculated that, after allo-SCT or ASCT when the tumor load is low, lymphocyte infusion will help restore immune capacity through the expansion of low levels of Treg and CD8 + cells, and vaccination at this time can trigger tumor antigen-specific immunity [ 79 ]. Cohen et al [ 80 ] recruited 13 patients with MM (NCT01380145) to apply autologous lymphocyte infusion and peri-ASCT immunotherapy with MAGE-A3 vaccination. The combined immunotherapy produced high titers in humoral immunity and strong antigen-specific CD4 + T cell responses in all subjects, and the responses could last for at least one year after ASCT.…”

Deregulation of Adaptive T Cell Immunity in Multiple Myeloma: Insights Into Mechanisms and Therapeutic Opportunities

“…In MM these approaches have been used in disease stages with lower tumor burden including stem cell transplantation (SCT), precursor disease such as smoldering myeloma (SMM), and MRD settings (141). In the setting of transplantation studies have evaluated vaccines targeting hTERT, MAGE-A3, or survivin in combination with vaccine-primed autologous lymphocyte infusion (142)(143)(144). In SMM a multi-peptide vaccine PVX-140 has been designed to induce a T cell mediated immune response by specifically stimulating CTLs with the tumor antigen targets X-box binding protein 1 (XBP1), Syndecan-1 (CD138), and SLAMF7 (CS1).…”