GM-CSF secreting leukemia cell vaccination for MDS/AML after allogeneic HSCT: a randomized, double-blinded, phase 2 trial

Vincent T Ho, Haesook T Kim, Jennifer Brock, Ilene Galinsky, Heather Daley, Carol Reynolds, Augustine Weber, Olga Pozdnyakova, Mariano Severgnini, Sarah Nikiforow, Corey Cutler, John Koreth, Edwin P Alyea, Joseph H Antin, Mahasweta Gooptu, Rizwan Romee, Roman Shapiro, Yi-Bin Chen, Jacalyn Rosenblatt, David Avigan, F Stephen Hodi, Glenn Dranoff, Catherine J Wu, Jerome Ritz, Robert J Soiffer, Vincent T Ho, Haesook T Kim, Jennifer Brock, Ilene Galinsky, Heather Daley, Carol Reynolds, Augustine Weber, Olga Pozdnyakova, Mariano Severgnini, Sarah Nikiforow, Corey Cutler, John Koreth, Edwin P Alyea, Joseph H Antin, Mahasweta Gooptu, Rizwan Romee, Roman Shapiro, Yi-Bin Chen, Jacalyn Rosenblatt, David Avigan, F Stephen Hodi, Glenn Dranoff, Catherine J Wu, Jerome Ritz, Robert J Soiffer

Abstract

Vaccination using irradiated, adenovirus transduced autologous myeloblasts to secrete granulocyte-macrophage colony-stimulating factor (GVAX) early after allogeneic hematopoietic stem cell transplantation (HSCT) can induce potent immune responses. We conducted a randomized phase 2 trial of GVAX after HSCT for myelodysplastic syndrome with excess blasts or relapsed/refractory acute myeloid leukemia. Myeloblasts were harvested before HSCT to generate the vaccine. Randomization to GVAX vs placebo (1:1) was stratified according to disease, transplant center, and conditioning. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate. GVAX or placebo vaccination was started between day 30 and 45 if there was engraftment and no GVHD. Vaccines were administered subcutaneously/intradermally weekly × 3, then every 2 weeks × 3. Tacrolimus taper began after vaccine completion. A total of 123 patients were enrolled, 92 proceeded to HSCT, and 57 (GVAX, n = 30; placebo, n = 27) received at least 1 vaccination. No Common Toxicity Criteria grade 3 or worse vaccine-related adverse events were reported, but injection site reactions were more common after GVAX (10 vs 1; P = .006). With a median follow-up of 39 months (range, 9-89 months), 18-month progression-free survival, overall survival, and relapse incidence were 53% vs 55% (P = .79), 63% vs 59% (P = .86), and 30% vs 37% (P = .51) for GVAX and placebo, respectively. Nonrelapse mortality at 18 months was 17% vs 7.7% (P = .18), grade II to IV acute GVHD at 12 months was 34% vs 12% (P = .13), and chronic GVHD at 3 years was 49% vs 57% for GVAX and placebo (P = .26). Reconstitution of T, B, and natural killer cells was not decreased or enhanced by GVAX. There were no differences in serum major histocompatibility chain-related protein A/B or other immune biomarkers between GVAX and placebo. GVAX does not improve survival after HSCT for myelodysplastic syndrome/acute myeloid leukemia. This trial was registered at www.clinicaltrials.gov as #NCT01773395.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Study flow diagram.
Figure 2.
Figure 2.
Treatment outcomes after HSCT and GVAX vs placebo vaccinations. PFS (A), OS (B), NRM (C), and relapse (D) after HSCT with GVAX vs placebo.
Figure 3.
Figure 3.
Transplant and vaccination outcomes stratified according to conditioning intensity. (A) PFS. (B) OS.
Figure 4.
Figure 4.
Reconstitution of immune cell subsets after HSCT and GVAX vs placebo vaccinations. ALC, absolute lymphocyte count; BMT, bone marrow transplantation; WBC, white blood cell count.

References

    1. Gooley TA, Chien JW, Pergam SA, et al. . Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363(22):2091-2101.
    1. Klebanoff CA, Finkelstein SE, Surman DR, et al. . IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci USA. 2004;101(7):1969-1974.
    1. Alpdogan O, Eng JM, Muriglan SJ, et al. . Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation. Blood. 2005;105(2):865-873.
    1. Reddy V, Winer AG, Eksioglu E, Meier-Kriesche HU, Schold JD, Wingard JR. Interleukin 12 is associated with reduced relapse without increased incidence of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11(12):1014-1021.
    1. Sportès C, Hakim FT, Memon SA, et al. . Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med. 2008;205(7):1701-1714.
    1. Dranoff G, Jaffee E, Lazenby A, et al. . Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA. 1993;90(8):3539-3543.
    1. Soiffer R, Hodi FS, Haluska F, et al. . Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma. J Clin Oncol. 2003;21(17):3343-3350.
    1. Soiffer R, Lynch T, Mihm M, et al. . Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc Natl Acad Sci USA. 1998;95(22):13141-13146.
    1. DeAngelo D, Alyea E, Borrello I, et al. . Posttransplant immunotherapy with a GM-CSF-based tumor vaccine (GVAX) following autologous stem cell transplant (ASCT) for acute myeloid leukemia (AML). Blood. 2004;104(11):441.
    1. DeAngelo D, Dranoff G, Galinsky I, et al. . A phase I study of vaccination with lethally irradiated, autologous myeloblasts engineered by adenoviral mediated gene transfer to secrete human granulocyte-macrophage colony stimulating factor. Blood. 2001;98(11). Abstract 1935.
    1. Jinushi M, Hodi FS, Dranoff G. Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. Proc Natl Acad Sci USA. 2006;103(24):9190-9195.
    1. Levitsky HI, Montgomery J, Ahmadzadeh M, et al. . Immunization with granulocyte-macrophage colony-stimulating factor-transduced, but not B7-1-transduced, lymphoma cells primes idiotype-specific T cells and generates potent systemic antitumor immunity. J Immunol. 1996;156(10):3858-3865.
    1. Schmollinger JC, Vonderheide RH, Hoar KM, et al. . Melanoma inhibitor of apoptosis protein (ML-IAP) is a target for immune-mediated tumor destruction. Proc Natl Acad Sci USA. 2003;100(6):3398-3403.
    1. Schoenfeld J, Jinushi M, Nakazaki Y, et al. . Active immunotherapy induces antibody responses that target tumor angiogenesis. Cancer Res. 2010;70(24):10150-10160.
    1. Teshima T, Mach N, Hill GR, et al. . Tumor cell vaccine elicits potent antitumor immunity after allogeneic T-cell-depleted bone marrow transplantation. Cancer Res. 2001;61(1):162-171.
    1. Ho VT, Vanneman M, Kim H, et al. . Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation. Proc Natl Acad Sci USA. 2009;106(37):15825-15830.
    1. Piesche M, Ho VT, Kim H, et al. . Angiogenic cytokines are antibody targets during graft-versus-leukemia reactions. Clin Cancer Res. 2015;21(5):1010-1018.
    1. Salgia R, Lynch T, Skarin A, et al. . Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma. J Clin Oncol. 2003;21(4):624-630.
    1. Przepiorka D, Weisdorf D, Martin P, et al. . 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15(6):825-828.
    1. Alho AC, Kim HT, Chammas MJ, et al. . Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood. 2016;127(5):646-657.
    1. Rambaldi B, Kim HT, Reynolds C, et al. . Impaired T- and NK-cell reconstitution after haploidentical HCT with posttransplant cyclophosphamide. Blood Adv. 2021;5(2):352-364.
    1. Do KT, Manuszak C, Thrash E, et al. . Immune modulating activity of the CHK1 inhibitor prexasertib and anti-PD-L1 antibody LY3300054 in patients with high-grade serous ovarian cancer and other solid tumors. Cancer Immunol Immunother. 2021;70(10):2991-3000.
    1. Tyan K, Baginska J, Brainard M, et al. . Cytokine changes during immune-related adverse events and corticosteroid treatment in melanoma patients receiving immune checkpoint inhibitors. Cancer Immunol Immunother. 2021;70(8):2209-2221.
    1. Kim HT, Gray R. Three-component cure rate model for nonproportional hazards alternative in the design of randomized clinical trials. Clin Trials. 2012;9(2):155-163.
    1. Breiman LFJ, Olshen RA, Stone CJ. Classification and Regression Trees: Wadsworth Statistics/Probability. 1st ed. Boca Raton, FL: Chapman and Hall/CRC; 1984.
    1. Therneau TM, Atkinson E. An Introduction to Recursive Partitioning Using the RPART Routines. Rochester, MN: Mayo Clinic; 1997.
    1. Simons JW, Mikhak B, Chang JF, et al. . Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer. Cancer Res. 1999;59(20):5160-5168.
    1. Nemunaitis J, Sterman D, Jablons D, et al. . Granulocyte-macrophage colony-stimulating factor gene-modified autologous tumor vaccines in non-small-cell lung cancer. J Natl Cancer Inst. 2004;96(4):326-331.
    1. Goldberg JM, Fisher DE, Demetri GD, et al. . Biologic activity of autologous, granulocyte-macrophage colony-stimulating factor secreting alveolar soft-part sarcoma and clear cell sarcoma vaccines. Clin Cancer Res. 2015;21(14):3178-3186.
    1. Zheng L, Ding D, Edil BH, et al. . Vaccine-induced intratumoral lymphoid aggregates correlate with survival following treatment with a neoadjuvant and adjuvant vaccine in patients with resectable pancreatic adenocarcinoma. Clin Cancer Res. 2021;27(5):1278-1286.
    1. Le DT, Picozzi VJ, Ko AH, et al. . Results from a Phase IIb, randomized, multicenter study of GVAX pancreas and CRS-207 compared with chemotherapy in adults with previously treated metastatic pancreatic adenocarcinoma (ECLIPSE study). Clin Cancer Res. 2019;25(18):5493-5502.
    1. Wu AA, Bever KM, Ho WJ, et al. . A phase II study of allogeneic GM-CSF-transfected pancreatic tumor vaccine (GVAX) with ipilimumab as maintenance treatment for metastatic pancreatic cancer. Clin Cancer Res. 2020;26(19):5129-5139.
    1. Obradovic AZ, Dallos MC, Zahurak ML, et al. . T-cell infiltration and adaptive Treg resistance in response to androgen deprivation with or without vaccination in localized prostate cancer. Clin Cancer Res. 2020;26(13):3182-3192.
    1. Serafini P, Carbley R, Noonan KA, Tan G, Bronte V, Borrello I. High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Res. 2004;64(17):6337-6343.
    1. Filipazzi P, Valenti R, Huber V, et al. . Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol. 2007;25(18):2546-2553.

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