Immunotransplant

Immunotransplant is a maneuver used to make vaccines more powerful. It refers to the process of infusing vaccine-primed T lymphocytes into lymphodepleted recipients for the purpose of enhancing the proliferation and function of those T cells and increasing immune protection induced by that vaccine.

The concept takes advantage of data from animal and studies in vaccinology and the homeostasis of T cells and has applications in the treatment of infectious disease, immunodeficiency syndromes, and cancer.

Basic Immunology

Vaccines

Historically, the effect of vaccines -particularly against pathogens- has been assessed by measurement of their induction of a B-cell-mediated -or humoral- immune response, i.e. the production of pathogen-specific antibodies. In the study of both infectious diseases and cancer, a majority of potential immune targets are only expressed intra-cellularly, and are thus inaccessible to antibody-mediated elimination. T-cell mediated immunity, by contrast, has the potential to recognize targets expressed either extra- or intra-cellularly and has therefore been studied extensively for treatment of these diseases.

A number of pre-clinical and clinical studies have demonstrated that vaccines against pathogens, bystander (non-pathogenic) proteins, tumor-associated antigens, or whole tumor cells, can induce specific T-cell mediated immune responses.[1][2][3][4][5][6] A number of approaches have been considered to amplify T cell mediated immune responses(e.g. IL-2, CTLA-4, IL-7, CD137), and some of these have shown clinical efficacy in eliminating particular types of cancer, most notably melanoma and renal cell carcinoma.

T-Cell Homeostasis and Homeostatic Proliferation

The use of immunotransplant to enhance T cell-mediated immune responses, derive from studies of T cell homeostasis. The total cohort of T cells in an organism maintain homeostasis – a consistent total number of T cells in the peripheral blood. Transient elevations in peripheral blood T cell counts cause the whole population to diminish, transient depletions cause the whole population to proliferate, generally maintaining a roughly total T cell count. The latter situation –lymphodepletion– has been studied extensively and the proliferation of mature T cells upon transfer into the lymphopenic host is referred to as “lymphodepletion-induced” or “homeostatic” proliferation.[7] It has been shown that homeostatic proliferation induces not only quantitative changes in T cell cohorts, but qualitative changes as well, such as increased function and the development of a memory-cell phenotype.[8] The mechanism of these changes has been shown to be primarily due to upregulation of a group of cytokines including IL-7 and IL-15 induced by lymphodepletion. Additionally, lymphodepletion is a non-selective method of eliminating several known regulatory, or immunosuppressive, subsets of immune cells, such as regulatory T cells.[9]

Clinical Trials Of T-Cell Adoptive Transfer

These observations have prompted several clinical studies of infusing pathogen- or tumor-specific T cells into lymphodepleted patients. A group at the National Cancer Institute demonstrated remarkable efficacy by infusing melanoma-specific T cells (obtained by growing tumor-infiltrating T cells ex vivo) into melanoma patients treated with lymphodepleting chemotherapy. In a series of studies (to 2005) of this approach, up to 70% of treated patients were shown to have regressions of their tumors, many of which had been considerable in size and refractory to other therapies.[10][11] These findings compare favorably with standard-of-care therapies for melanoma which generally lead to tumor regressions in only ~10-12% of patients.

Pre-Clinical Studies And Clinical Trials Of Vaccine-Primed T-Cell Adoptive Transfer (I.E. Immunotransplant)

Because of the logistic difficulty of obtaining tumor-specific T cells via the ex vivo expansion of tumor-infiltrating cells, a number of studies have examined inducing these cells in vivo by vaccination. Levitsky et al., at Johns Hopkins, in a series of pre-clinical studies demonstrated that vaccine-induced T cells could be considerably more effective when re-infused into lymphodepleted recipients.[12][13] Subsequently, a clinical study in patients with multiple myeloma conducted by June et al., demonstrated that a standard vaccination against pneumonia could induce a T-cell-mediated response to the vaccine and that re-infusing these T cells after an extremely lymphodepletive therapy –autologous stem cell transplant – could significantly enhance that response.[14]

To expand this immunotransplant concept to the amplification of anti-cancer immunity, researchers at Stanford University developed a pre-clinical lymphoma model using a in situ, CpG-base vaccine[15] to induce anti-tumor immunity and demonstrated that this immunity was enhanced 10-40 fold by immunotransplant.[16] The above studies by Levitsky et al., were an important precedent for this work. In fact the Hopkins published preliminary results of a clinical study testing the basic immunotransplant concept in acute myeloid leukemia [17] demonstrating encouraging signals of enhanced anti-tumor immunity.[18] To continue the clinical translation of this approach, in August 2009 the Stanford group[19] initiated a phase I/II clinical trial for patients with newly diagnosed mantle cell lymphoma.[20] That study uses a whole-cell, CpG-activated, autologous tumor vaccine to induce anti-tumor immunity followed by leukapheresis and re-infusion of the vaccine-primed cells immediately after standard autologous transplant. Initial results of this study were presented at the ASCO 2011 Annual Meeting showing successful data towards the primary endpoint: amplification of anti-tumor T-cell responses. [21]

See also

• Vaccine
• Immunology
• T-Cell
• CpG

References

1. Neelapu SS, Kwak LW, Kobrin CB, et al. Vaccine-induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma. Nat Med 2005;11(9):986-91.
2. Biagi E, Rousseau R, Yvon E, et al. Responses to human CD40 ligand/human interleukin-2 autologous cell vaccine in patients with B-cell chronic lymphocytic leukemia. Clin Cancer Res 2005;11(19 Pt 1):6916-23.
3. Monsurro V, Nagorsen D, Wang E, et al. Functional heterogeneity of vaccine-induced CD8(+) T cells. J Immunol 2002;168(11):5933-42.
4. Dudley ME, Nishimura MI, Holt AK, Rosenberg SA. Antitumor immunization with a minimal peptide epitope (G9-209-2M) leads to a functionally heterogeneous CTL response. J Immunother 1999;22(4):288-98.
5. Berd D, Sato T, Cohn H, Maguire HC, Jr., Mastrangelo MJ. Treatment of metastatic melanoma with autologous, hapten-modified melanoma vaccine: regression of pulmonary metastases. Int J Cancer 2001;94(4):531-9.
6. Rousseau RF, Biagi E, Dutour A, et al. Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation. Blood 2006;107(4):1332-41.
7. Wrzesinski C, Restifo NP. Less is more: lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy. Curr Opin Immunol 2005;17(2):195-201.
8. Hamilton SE, Wolkers MC, Schoenberger SP, Jameson SC. The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nat Immunol 2006;7(5):475-81.
9. Ghiringhelli F, Larmonier N, Schmitt E, et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 2004;34(2):336-44.
10. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23(10):2346-57.
11. Dudley ME, Yang JC, Sherry R, et al. Adoptive Cell Therapy for Patients With Metastatic Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative Regimens. J Clin Oncol 2008.
12. Borrello I, Sotomayor EM, Rattis FM, Cooke SK, Gu L, Levitsky HI. Sustaining the graft-versus-tumor effect through posttransplant immunization with granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing tumor vaccines. Blood 2000;95(10):3011-9.
13. Mirmonsef P, Tan G, Zhou G, et al. Escape from suppression: tumor-specific effector cells outcompete regulatory T cells following stem-cell transplantation. Blood 2008;111(4):2112-21.
14. Rapoport AP, Stadtmauer EA, Aqui N, et al. Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med 2005;11(11):1230-7.
15. Li J, Song W, Czerwinski DK, et al. Lymphoma immunotherapy with CpG oligodeoxynucleotides requires TLR9 either in the host or in the tumor itself. J Immunol 2007;179(4):2493-500.
16. Brody JD, Goldstein MJ, Czerwinski DK, Levy R. Immunotransplantation preferentially expands T-effector cells over T-regulatory cells and cures large lymphoma tumors. Blood 2009;113(1):85-94.
17. ClinicalTrials.gov: NCT00116467
18. Borrello IM, Levitsky HI, Stock W, et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting cellular immunotherapy in combination with autologous stem cell transplantation (ASCT) as postremission therapy for acute myeloid leukemia (AML). Blood 2009;114(9):1736-45.
19. "Phase I/II of a CpG-Activated Whole Cell Vaccine Followed by Autologous "Immunotransplant" for MCL". Archived from the original on 2011-06-09. Retrieved 2009-09-22.
20. ClinicalTrials.gov ID:NCT00490529
21. http://media.asco.org/player/flashplayer/player.aspx?LectureID=59241&conferenceFolder=am2011&SessionFolder=6619&configFile=config_akamai.xml&IMISID=67882&UserIP=171.65.6.4&cs=[vm_102_9_4106_59241__]