Neoantigen and tumor antigen-specific immunity transferred from immunized donors is detectable early after allogeneic transplantation in myeloma patients
M Foglietta, S S Neelapu, L W Kwak, Y Jiang, D Nattamai, S-T Lee, D H Fowler, C Sportes, R E Gress, S M Steinberg, L M Vence, L Radvanyi, K C Dwyer, M H Qazilbash, R N K Bryant, M R Bishop, M Foglietta, S S Neelapu, L W Kwak, Y Jiang, D Nattamai, S-T Lee, D H Fowler, C Sportes, R E Gress, S M Steinberg, L M Vence, L Radvanyi, K C Dwyer, M H Qazilbash, R N K Bryant, M R Bishop
Abstract
To enhance the therapeutic index of allogeneic hematopoietic SCT (HSCT), we immunized 10 HLA-matched sibling donors before stem cell collection with recipient-derived clonal myeloma Ig, idiotype (Id), as a tumor antigen, conjugated with keyhole limpet hemocyanin (KLH). Vaccinations were safe in donors and recipients. Donor-derived KLH- and Id-specific humoral and central and effector memory T-cell responses were detectable by day 30 after HSCT and were boosted by post-transplant vaccinations at 3 months in most recipients. One patient died before booster vaccinations. Specifically, after completing treatment, 8/9 myeloma recipients had persistent Id-specific immune responses and 5/9 had improvement in disease status. Although regulatory T cells increased after vaccination, they did not impact immune responses. At a median potential follow-up period of 74 months, 6 patients are alive, the 10 patients have a median PFS of 28.5 months and median OS has not been reached. Our results provide proof of principle that neoantigen and tumor antigen-specific humoral and cellular immunity could be safely induced in HSCT donors and passively transferred to recipients. This general strategy may be used to reduce relapse of malignancies and augment protection against infections after allogeneic HSCT.
Conflict of interest statement
CONFLICTS OF INTEREST
The authors declare that there are no competing financial interests.
Figures
References
- Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature. 2001;411(6835):385–389.
- Copelan EA. Hematopoietic stem-cell transplantation. The New England journal of medicine. 2006;354(17):1813–1826.
- Giaccone L, Storer B, Patriarca F, Rotta M, Sorasio R, Allione B, et al. Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma. Blood. 2011;117(24):6721–6727.
- Crawley C, Iacobelli S, Bjorkstrand B, Apperley JF, Niederwieser D, Gahrton G. Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning. Blood. 2007;109(8):3588–3594.
- Lynch RG, Graff RJ, Sirisinha S, Simms ES, Eisen HN. Myeloma proteins as tumor-specific transplantation antigens. Proceedings of the National Academy of Sciences of the United States of America. 1972;69(6):1540–1544.
- Stevenson GT, Stevenson FK. Antibody to a molecularly-defined antigen confined to a tumour cell surface. Nature. 1975;254(5502):714–716.
- Bendandi M, Gocke CD, Kobrin CB, Benko FA, Sternas LA, Pennington R, et al. Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nature medicine. 1999;5(10):1171–1177.
- Neelapu SS, Kwak LW, Kobrin CB, Reynolds CW, Janik JE, Dunleavy K, et al. Vaccine-induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma. Nature medicine. 2005;11(9):986–991.
- Schuster SJ, Neelapu SS, Gause BL, Janik JE, Muggia FM, Gockerman JP, et al. Vaccination With Patient-Specific Tumor-Derived Antigen in First Remission Improves Disease-Free Survival in Follicular Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(20):2787–2794.
- Reichardt VL, Okada CY, Liso A, Benike CJ, Stockerl-Goldstein KE, Engleman EG, et al. Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma--a feasibility study. Blood. 1999;93(7):2411–2419.
- Massaia M, Borrione P, Battaglio S, Mariani S, Beggiato E, Napoli P, et al. Idiotype vaccination in human myeloma: generation of tumor-specific immune responses after high-dose chemotherapy. Blood. 1999;94(2):673–683.
- Bendandi M, Rodriguez-Calvillo M, Inoges S, Lopez-Diaz de Cerio A, Perez-Simon JA, Rodriguez-Caballero A, et al. Combined vaccination with idiotype-pulsed allogeneic dendritic cells and soluble protein idiotype for multiple myeloma patients relapsing after reduced-intensity conditioning allogeneic stem cell transplantation. Leukemia & lymphoma. 2006;47(1):29–37.
- Kwak LW, Pennington R, Longo DL. Active immunization of murine allogeneic bone marrow transplant donors with B-cell tumor-derived idiotype: a strategy for enhancing the specific antitumor effect of marrow grafts. Blood. 1996;87(7):3053–3060.
- Hornung RL, Longo DL, Bowersox OC, Kwak LW. Tumor antigen-specific immunization of bone marrow transplantation donors as adoptive therapy against established tumor. Journal of the National Cancer Institute. 1995;87(17):1289–1296.
- Kwak LW, Taub DD, Duffey PL, Bensinger WI, Bryant EM, Reynolds CW, et al. Transfer of myeloma idiotype-specific immunity from an actively immunised marrow donor. Lancet. 1995;345(8956):1016–1020.
- Neelapu SS, Munshi NC, Jagannath S, Watson TM, Pennington R, Reynolds C, et al. Tumor antigen immunization of sibling stem cell transplant donors in multiple myeloma. Bone marrow transplantation. 2005;36(4):315–323.
- Cabrera R, Diaz-Espada F, Barrios Y, Briz M, Fores R, Barbolla L, et al. Infusion of lymphocytes obtained from a donor immunised with the paraprotein idiotype as a treatment in a relapsed myeloma. Bone marrow transplantation. 2000;25(10):1105–1108.
- Kwak LW, Neelapu SS, Bishop MR. Adoptive immunotherapy with antigen-specific T cells in myeloma: a model of tumor-specific donor lymphocyte infusion. Seminars in oncology. 2004;31(1):37–46.
- Ottinger HD, Beelen DW, Scheulen B, Schaefer UW, Grosse-Wilde H. Improved immune reconstitution after allotransplantation of peripheral blood stem cells instead of bone marrow. Blood. 1996;88(7):2775–2779.
- Storek J, Witherspoon RP, Maloney DG, Chauncey TR, Storb R. Improved reconstitution of CD4 T cells and B cells but worsened reconstitution of serum IgG levels after allogeneic transplantation of blood stem cells instead of marrow. Blood. 1997;89(10):3891–3893.
- Storek J, Dawson MA, Storer B, Stevens-Ayers T, Maloney DG, Marr KA, et al. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood. 2001;97(11):3380–3389.
- Jamshed S, Fowler DH, Neelapu SS, Dean RM, Steinberg SM, Odom J, et al. EPOCH-F: a novel salvage regimen for multiple myeloma before reduced-intensity allogeneic hematopoietic SCT. Bone marrow transplantation. 2011;46(5):676–681.
- Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. British journal of haematology. 1998;102(5):1115–1123.
- Wieczorek G, Asemissen A, Model F, Turbachova I, Floess S, Liebenberg V, et al. Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer research. 2009;69(2):599–608.
- Wimperis JZ, Brenner MK, Prentice HG, Reittie JE, Karayiannis P, Griffiths PD, et al. Transfer of a functioning humoral immune system in transplantation of T-lymphocyte-depleted bone marrow. Lancet. 1986;1(8477):339–343.
- Lum LG, Seigneuret MC, Storb R. The transfer of antigen-specific humoral immunity from marrow donors to marrow recipients. Journal of clinical immunology. 1986;6(5):389–396.
- Molrine DC, Guinan EC, Antin JH, Parsons SK, Weinstein HJ, Wheeler C, et al. Donor immunization with Haemophilus influenzae type b (HIB)-conjugate vaccine in allogeneic bone marrow transplantation. Blood. 1996;87(7):3012–3018.
- Molrine DC, Antin JH, Guinan EC, Soiffer RJ, MacDonald K, Malley R, et al. Donor immunization with pneumococcal conjugate vaccine and early protective antibody responses following allogeneic hematopoietic cell transplantation. Blood. 2003;101(3):831–836.
- Storek J, Dawson MA, Lim LC, Burman BE, Stevens-Ayers T, Viganego F, et al. Efficacy of donor vaccination before hematopoietic cell transplantation and recipient vaccination both before and early after transplantation. Bone marrow transplantation. 2004;33(3):337–346.
- Parkkali T, Kayhty H, Hovi T, Olander RM, Roivainen M, Volin L, et al. A randomized study on donor immunization with tetanus-diphtheria, Haemophilus influenzae type b and inactivated poliovirus vaccines to improve the recipient responses to the same vaccines after allogeneic bone marrow transplantation. Bone marrow transplantation. 2007;39(3):179–188.
- Lucas KG, Small TN, Heller G, Dupont B, O'Reilly RJ. The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation. Blood. 1996;87(6):2594–2603.
- Kato S, Yabe H, Yabe M, Kimura M, Ito M, Tsuchida F, et al. Studies on transfer of varicella-zoster-virus specific T-cell immunity from bone marrow donor to recipient. Blood. 1990;75(3):806–809.
- Leen AM, Christin A, Myers GD, Liu H, Cruz CR, Hanley PJ, et al. Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation. Blood. 2009;114(19):4283–4292.
- Zandvliet ML, Falkenburg JH, van Liempt E, Veltrop-Duits LA, Lankester AC, Kalpoe JS, et al. Combined CD8+ and CD4+ adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection. Haematologica. 2010;95(11):1943–1951.
- Bertinetti C, Zirlik K, Heining-Mikesch K, Ihorst G, Dierbach H, Waller CF, et al. Phase I trial of a novel intradermal idiotype vaccine in patients with advanced B-cell lymphoma: specific immune responses despite profound immunosuppression. Cancer research. 2006;66(8):4496–4502.
- Inoges S, Rodriguez-Calvillo M, Zabalegui N, Lopez-Diaz de Cerio A, Villanueva H, Soria E, et al. Clinical benefit associated with idiotypic vaccination in patients with follicular lymphoma. Journal of the National Cancer Institute. 2006;98(18):1292–1301.
- Navarrete MA, Heining-Mikesch K, Schuler F, Bertinetti-Lapatki C, Ihorst G, Keppler-Hafkemeyer A, et al. Upfront immunization with autologous recombinant idiotype Fab fragment without prior cytoreduction in indolent B-cell lymphoma. Blood. 2011;117(5):1483–1491.
- De Groot AS, Moise L, McMurry JA, Wambre E, Van Overtvelt L, Moingeon P, et al. Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes". Blood. 2008;112(8):3303–3311.
- Warncke M, Buchner M, Thaller G, Dodero A, Bulashevska A, Pfeifer D, et al. Control of the specificity of T cell-mediated anti-idiotype immunity by natural regulatory T cells. Cancer immunology, immunotherapy : CII. 2011;60(1):49–60.
- Teshima T, Mach N, Hill GR, Pan L, Gillessen S, Dranoff G, et al. Tumor cell vaccine elicits potent antitumor immunity after allogeneic T-cell-depleted bone marrow transplantation. Cancer research. 2001;61(1):162–171.
- Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. The Journal of experimental medicine. 2005;202(7):907–912.
Source: PubMed