1.HLA mismatched alloresponses: Exploiting the GVL potential of the haploidentical donor: We previously characterized the mismatched alloresponse in man and showed that T-cell responses to allogeneic targets arise predominantly from the nave pool of post-thymic T cells. We are continuing a trial of haploidentical donor lymphocyte transfusions with stem cell rescue in patients who relapse after SCT. We have shown in 4 patients a powerful graft-versus-marrow effect of these infusions but patients all died later from recurrence of disease or complications associated with poor hematopoietic recovery. This study is ongoing. We now plan to extend this approach to optimize the GVL effect of SCT. We have designed haploidentical SCT protocol to treat patients with high risk leukemias. The patients will receive a transplant from a haploidentical family donor. GVHD will be mitigated by treating the donor with low dose Interleukin 2 (IL-2) to increase regulatory T cells in the graft and the patient will receive low dose IL-2 for the first few months post transplant to maintain Treg levels and prevent GVHD. We will test whether this approach permits the development of strong GVL immunity monitoring antileukemic responses and relapse rates after transplant. This protocol is planned to open in 2014. 2.Generating clinical grade Leukemia-specific T cells: We are studying expansion techniques for leukemia-specific T cells with peptide mixes of WT1, proteinase 3, PRAME, MAGE3, and aurora-A kinase.
The aim i s to develop a clinical grade system to generate off the shelf donor or third party tumor-specific T cells for infusion in SCT recipients to treat or prevent relapse. Preliminary data indicates that individual responses to the tumor peptides are variable, but that all healthy donors tested make a response to a mix of LAA peptides indicating that this technique can be developed as a robust clinically applicable approach to treating patients at high risk of relapse after SCT with leukemia reactive T cell infusions. Translational work to expand the process to clinical scale are under way. To further increase the clinical potential of adoptive T cell therapy we have constructed a panel of artificial antigen presenting cells (AAPC) based upon the K562 CML cell line. These AAPC have the potential to induce T cell responses to antigens presented by gene inserted HAL A2 and HLA DR15 together with CD80 and CD81 costimulatory molecules. However we found that K562 cells produce a suppressor which blocks T cell proliferation. Suppression can be blocked by fixation which preserves the stimulatory function of the AAPC. We are currently studying the nature of T cell suppression by K562 cells and continuing to develop a clinical grade off the shelf AAPC for expansion of T cells for adoptive therapy. A library of K562 cells transfected with a panel of HLA class I and II antigens has been created and will be used to generate T cells recognizing innate and transfected leukemia antigens. 3. New antigen discovery: In conjunction with Dr Chris Hourigan we are screening AML samples obtained from collaboration with Vanderbilt University (Dr Strickland) to characterize the pattern of LAA presentation on AML stem cells and identify new LAA. These findings will assist the construction of a broad antigen library capable of inducing T cell responses to the majority of AML patients.
|Whitehill, Greg D; Amarnath, Shoba; Muranski, Pawel et al. (2016) Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While Conserving Immunity to Viruses and Leukemia. Mol Ther :|
|Barrett, Gene R; Thibodeaux, Kasey E; Replogle, William H et al. (2015) Body Mass Index as an Indicator of Associated Intra-articular Injuries in Patients With Anterior Cruciate Ligament Tears. J Surg Orthop Adv 24:159-63|
|Barrett, Austin John (2015) A new checkpoint in the path to GVHD? How bedside-to-bench stem cell transplant studies can inform human GVHD biology. J Leukoc Biol 97:213-5|
|Ito, Sawa; Barrett, A John; Dutra, Amalia et al. (2015) Long term maintenance of myeloid leukemic stem cells cultured with unrelated human mesenchymal stromal cells. Stem Cell Res 14:95-104|
|Goswami, M; McGowan, K S; Lu, K et al. (2015) A multigene array for measurable residual disease detection in AML patients undergoing SCT. Bone Marrow Transplant 50:642-51|
|Barrett, Austin J (2015) Tailoring steroid-sensitive virus-specific T cells with TALEN. Blood 126:2767-8|
|Kerkar, Sid P; Chinnasamy, Dhanalakshmi; Hadi, Neima et al. (2014) Timing and intensity of exposure to interferon-Î³ critically determines the function of monocyte-derived dendritic cells. Immunology 143:96-108|
|Weber, G; Gerdemann, U; Caruana, I et al. (2013) Generation of multi-leukemia antigen-specific T cells to enhance the graft-versus-leukemia effect after allogeneic stem cell transplant. Leukemia 27:1538-47|
|Weber, Gerrit; Caruana, Ignazio; Rouce, Rayne H et al. (2013) Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia--implications for immunotherapy. Clin Cancer Res 19:5079-91|
|Falkenburg, Willem J J; Melenhorst, J Joseph; van de Meent, Marian et al. (2011) Allogeneic HLA-A*02-restricted WT1-specific T cells from mismatched donors are highly reactive but show off-target promiscuity. J Immunol 187:2824-33|
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