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Clinical Trial
. 2014 Mar 1;20(5):1355-65.
doi: 10.1158/1078-0432.CCR-13-2817. Epub 2014 Feb 11.

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

Aaron P Rapoport  1 , Nicole A Aqui, Edward A Stadtmauer, Dan T Vogl, Yin Yan Xu, Michael Kalos, Ling Cai, Hong-Bin Fang, Brendan M Weiss, Ashraf Badros, Saul Yanovich, Gorgun Akpek, Patricia Tsao, Alan Cross, Dean Mann, Sunita Philip, Naseem Kerr, Andrea Brennan, Zhaohui Zheng, Kathleen Ruehle, Todd Milliron, Scott E Strome, Andres M Salazar, Bruce L Levine, Carl H June
Affiliations
Clinical Trial

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

Aaron P Rapoport et al. Clin Cancer Res. .

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.

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Figures

Figure 1
Figure 1
The trial design depicting the transplant and maintenance phases. Note that only one MAGE-A3 vaccination was given before T-cell collection and 5 Immunizations were given after transplant at days +14, +42, +90, +120, and +150. About 10 days (–14) elapsed between the first set of immunizations and the T-cell apheresis. Blood samples for immune monitoring were obtained at enrollment, the time of apheresis (T-cell collection), and days +14, +60, +100, and +1 80 after transplant.
Figure 2
Figure 2
EFS and OS curves.
Figure 3
Figure 3
Dextramer studies of T-cell responses against the MAGE-A3 Trojan peptide vaccine in patients with HLA-A2+ (N = 8 evaluable patients). A, pie charts show that 3 of 6 (50%) of evaluable patients with HLA-A2+ had positive dextramer staining with CTL-1 (class 1) dextramer on CD8+ T cells after culture with the CTL-1 peptide and 5 of 6 (83%) had positive dextramer staining with CTL-2 (class I) peptide after CTL-2 culture, whereas 7 of 8 evaluable patients had positive dextramer staining using either the CTL-1 or CTL-2 peptides after culture of cells with the whole vaccine. Note that peripheral blood samples for in vitro culture and dextramer staining were oblained at enrollment, day +2 (optionally), day +14, day +60, day +100, and day +180 after transplant; B, seriai dot plots show proportions of dextramer-positive CD8+ T cells after culture and staining for a specifie patient at multiple timepoints after ASCT.
Figure 4
Figure 4
Functional studies of T-cell responses to the MAGE-A3 Trojan peptide vaccine (N = 25 evaluable patients). A, bar graph showing the % IFN-γ-produclng CD4+ T cells at seriai timepoints for all evaluable patients (N = 25) after culture and restimulation with the MAGE-A3 whole vaccine; B, zoomed in view of CD4+ responses (0-1 % range); C, bar graph showing the % IFN-γ-producing CD8+ T cells at seriai timepoints for ail evaluable patients (N = 25) after culture and restimulation with the MAGE-A3 whole vaccine (0-1 % range shown, see Supplementary Fig. S2 for expanded bar graph); D, seriai dot plots show the proportions of IFN-γ-positive CD4+ T cells after culture and restimulation with whole MAGE-A3 vaccine (bottom) and the HTL (class II) peptide (top) for a specifie patient at multiple timepoints after ASCT.
Figure 5
Figure 5
ELISA assay for antibody responses to the MAGE-A3 Trojan peptide vaccine. Shown are box and whisker plots at multiple timepoints of the log transformed antibody titers for the cohort of 9 patients who received montanide in their vaccine formulations (yellow or left-sided boxes) versus the cohort of 18 patients who did not receive montanide (orange or right-sided boxes). Open circles denote outlier responses. The differences at days 100 and 180 were statistically significant with P < 0.0001.
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