Adoptive transfer of gene-modified autologous T-cells post-ASCT for myeloma

Summary

Principal Investigator: Aaron P Rapoport
Abstract: DESCRIPTION (provided by applicant): Myeloma remains largely incurable in spite of high-dose chemotherapy and autologous stem cell transplantation (ASCT) and targeted therapies. Retrospective studies suggest that better clinical outcomes may be associated with more rapid lymphocyte recovery during the early post-transplant period. In addition, tumor-reactive T-cells are present at low frequencies in the marrow or blood of untreated patients with myeloma. Thus, strategies to augment the recovery and function of autologous T-cells post-transplant may be clinically beneficial. Furthermore, they have the potential to synergize with current therapies to promote remissions and achieve long term disease free survival. We have conducted several trials of adoptive transfer T cell therapy for multiple myeloma, testing the hypothesis that improved T-cell recovery through intravenous infusion of ex-vivo CD28 costimulated T cells might provide a platform for post-transplant immunotherapy and enhance vaccine strategies. Autologous T-cells were stimulated by artificial antigen presenting cells under conditions that promote central memory cells and Th1/Tc1 function. In the first study, a 7-valent pneumococcal conjugate vaccine (PCV) was used as a well-defined antigen which allowed us to show that the adoptive transfer of in-vivo vaccine-primed and ex-vivo costimulated autologous T-cells early after transplant led to enhanced T-cell recovery and generated vaccine-specific T and B-cell responses. In the second study, this platform of combined vaccine and T-cell immunotherapy also generated immune responses in a significant proportion of patients against a putative tumor antigen vaccine composed of peptides derived from human telomerase (hTERT) and survivin. Currently, we are studying whether the frequency and magnitude of the myeloma-directed immune responses can be enhanced by using a different vaccine based on MAGE-A3 and a novel vaccine adjuvant called Poly-ICLC (a TLR-3 receptor agonist). However, there are at least two potential drawbacks of the approach that we have taken so far: i) the adoptively transferred T-cells are polyclonal and thus only a small proportion are truly directed against the myeloma tumor cells;and ii) the myeloma specificity depends on successful "priming" of the autologous T-cells prior to collection and costimulation/expansion, a process that is inefficient especially in the setting of active malignancy. To address these impediments to effective immunotherapy in this proposal, we will genetically modify autologous T-cells through transduction of lentiviral constructs which encode high-affinity T-cell receptors (TCRs) for two naturally processed epitopes that are derived from tumor antigens MAGE-A3 and NY-ESO-1. These cancer/testis tumor antigens (CTAgs) are frequently and specifically expressed in myeloma cells. We will specifically study whether these transduced cells can be safely transferred very soon after autologous stem cell transplantation (ASCT) and whether these gene-modified T-cells persist, function and target myeloma cells in patients. We will also use lenalidomide both as a post-transplant maintenance treatment for myeloma and as a possible immunomodulator. Recent work indicates that lenalidomide may have important immunostimulatory properties. If this study shows that TCR-gene modified T-cells are safe and functional then this combination strategy of ASCT followed by adoptive transfer of "redirected" autologous T-cells could be a platform for effective post-transplant immunotherapy of myeloma and perhaps other hematologic neoplasms.
Funding Period: 2012-09-01 - 2015-08-31
more information: NIH RePORT

Top Publications

  1. pmc Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma
    Gerald P Linette
    Siteman Cancer Center and Departments of Medicine and Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
    Blood 122:863-71. 2013

Research Grants

  1. Center for Interdisciplinary Research on Nicotine Addiction (CIRNA)
    Caryn Lerman; Fiscal Year: 2013
  2. MOLECULAR BASIS OF VIRAL AND CELLULAR TRANSFORMATION
    DANIEL C DIMAIO; Fiscal Year: 2013
  3. Directing Tumor-specific T cells to Tumors
    Pawel Kalinski; Fiscal Year: 2013
  4. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013
  5. MIXED HEMATOPOIETIC CHIMERISM AFTER STEM CELL ALLOGRAFTS
    Rainer F Storb; Fiscal Year: 2013
  6. Host Defense Against HIV-related Pulmonary Infections
    Judd E Shellito; Fiscal Year: 2013
  7. P53 - REGULATORS AND EFFECTORS
    Stuart A Aaronson; Fiscal Year: 2013
  8. Mayo SPORE in Brain Cancer
    BRIAN PATRICK O'NEILL; Fiscal Year: 2013
  9. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
  10. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013

Detail Information

Publications1

  1. pmc Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma
    Gerald P Linette
    Siteman Cancer Center and Departments of Medicine and Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
    Blood 122:863-71. 2013
    ..These patients demonstrate that TCR-engineered T cells can have serious and not readily predictable off-target and organ-specific toxicities and highlight the need for improved methods to define the specificity of engineered TCRs. ..

Research Grants30

  1. Center for Interdisciplinary Research on Nicotine Addiction (CIRNA)
    Caryn Lerman; Fiscal Year: 2013
    ..The CIRNA is proposed to replace the TTURC, since this NIH initiative is ending. ..
  2. MOLECULAR BASIS OF VIRAL AND CELLULAR TRANSFORMATION
    DANIEL C DIMAIO; Fiscal Year: 2013
    ..abstract_text> ..
  3. Directing Tumor-specific T cells to Tumors
    Pawel Kalinski; Fiscal Year: 2013
    ..abstract_text> ..
  4. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013
    ..By pooling our data, specimens, and importantly, expertise to investigate these synergist hypotheses, we will elucidate much of the etiology of aggressive, early onset breast cancers in AA women. ..
  5. MIXED HEMATOPOIETIC CHIMERISM AFTER STEM CELL ALLOGRAFTS
    Rainer F Storb; Fiscal Year: 2013
    ..This is especially important since median ages at diagnosis of patients with most candidate diseases range from 65 to 70 years, which is beyond the age range of inclusion in conventional myeloablative HCT regimens. ..
  6. Host Defense Against HIV-related Pulmonary Infections
    Judd E Shellito; Fiscal Year: 2013
    ..abstract_text> ..
  7. P53 - REGULATORS AND EFFECTORS
    Stuart A Aaronson; Fiscal Year: 2013
    ..This Program brings together a senior group of investigators from different disciplines and with complementary expertise focused on important and novel aspects of p53 biology. ..
  8. Mayo SPORE in Brain Cancer
    BRIAN PATRICK O'NEILL; Fiscal Year: 2013
    ..D.) D. Animal Core (Director: J.N. Sarkaria, M.D.;Co-Director: I.F. Parney, M.D., Ph.D.) E. Clinical Research Core (Director: J.C. Buckner, M.D.;Co-Director: D. H. Lachance, M.D.) Developmental Research Portfolio ..
  9. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
    ..We also want to understand why the immune system destroys hypocretin neurons in narcolepsy and to prevent/cure it. ..
  10. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  11. Therapeutic Opportunities for Pediatric Astrocytoma
    Rosalind A Segal; Fiscal Year: 2013
    ..The three projects interact with one another and are further unified by economies of scale enabled by an Innovative Neuropathology (INP) core. ..
  12. Normal &Neoplastic Growth in the Brain
    Suzanne J Baker; Fiscal Year: 2013
    ..Integrated analyses within the group will identify common and unique signal transduction pathways in pediatric brain tumorigenesis. ..
  13. VACCINE INDUCED IMMUNITY IN THE YOUNG AND AGED
    Rafi Ahmed; Fiscal Year: 2013
    ....
  14. Post-transplant vaccines to enhance graft-versus-leukemia responses
    CATHERINE JU YING WU; Fiscal Year: 2013
    ..End of Abstract) ..
  15. T-cell Therapy for B-lineage Acute Lymphoblastic Leukemia
    Laurence J N Cooper; Fiscal Year: 2013
    ..LAY SUMMARY: We will infuse CD19-specific T cells after transplantation to improve survival for patients with acute lymphoblastic leukemia. ..
  16. Immuno/Immuno-Gene Therapies for Thoracic Malignancies
    STEVEN MARK ALBELDA; Fiscal Year: 2013
    ..Core C will provide biostatistical and data management services. The goal of this P01 is to alter the treatment paradigm for MPM and advance the entire field of adoptive T cell transfer. ..
  17. Radiation Bystander Effects: Mechanisms
    Tom K Hei; Fiscal Year: 2013
    ..abstract_text> ..
  18. Martin Delaney Collaboratory to Eradicate HIV-1 Infection
    David M Margolis; Fiscal Year: 2013
    ..We are convinced that together we will catalyze advances that will ultimately lead to the eradication of HIV infection. ..
  19. Herpesviral, Oncogenesis, Latency and Reactivation
    NANCY JOAN RAAB-TRAUB; Fiscal Year: 2013
    ..abstract_text> ..
  20. Efficacy and safety of novel CD80 IL15 IL15Ra expressing autologous AML vaccines
    KARIN L GAENSLER; Fiscal Year: 2013
    ..Studies will directly inform the design of a Phase 1 clinical AML vaccine trial at UCSF for patients >60, ineligible for HSCT. ..
  21. Immunobioogy for Marrow Allografts for Leukemia
    RICHARD JOHN O'REILLY; Fiscal Year: 2013
    ..The 3 cores include: Core A which provides all patient samples and evaluate grafts pre and post HSCT, Core B Biostatistics and Core C administrative support and oversight. ..