Project 2: Circulating NKG2D + CD8 + T Cells Predicts Outcomes in Transplanted Myeloma Patients
Kenneth Meehan, MD
Mike Fanger, Paul Guyre, Marc Ernstoff, Jim Gorham
Multiple myeloma, the second most common hematologic malignancy, is incurable with standard therapy. In newly diagnosed patients, high-dose chemotherapy followed by autologous stem cell transplant improves survival. Lymphocyte reconstitution following transplant is a critical prognostic variable, since early lymphocyte recovery predicts improved survival. Our previous results indicate that the presence and the function of a critical population of CD8+T cells, called NKG2D+CD8+T cells, may determine the survival of transplanted myeloma patients. Thus, we hypothesize that treatments that increase the number and the function of circulating NKG2D+CD8+T cells should improve survival. We will conduct a multi-center randomized clinical trial to test our hypothesis with the following Aims:
- AIM 1 (Pre-transplant): We will evaluate whether immune mobilization with IL-2 and growth factors generates highly functional NKG2D+CD8+T cells in vivo by comparing the number, function, cytotoxic activity and mechanism(s) of killing of the mobilized NKG2D+CD8+T cells within the leukapheresis products of the immune-mobilized versus the standard mobilized cohorts.
- AIM 2 (Post-transplant): We will evaluate whether post-transplant IL-2 and GM-CSF continues to support circulating NKG2D+CD8+T cells by comparing the number and the function(s) of circulating NKG2D+CD8+T cells after transplant among the 4 groups.
- AIM 3 (Clinical Outcomes):Finally, we will test whether the number of NKG2D+CD8+T cells that are infused and circulating following transplant can predict response and survival.
Role of COBRE in career trajectory: The results from these experiments have lead to the publication of multiple manuscripts. COBRE funding has provided the PI with support to identify preliminary data used to submit a number of grant applications.
Meehan KR, Wu J, Bengtson E, Hill JM, Ely P, Szczepiorkowski ZM., Ernstoff MS. Early Recovery of Aggressive Cytotoxic Cells and Improved Immune Resurgence with Post-Transplant Immunotherapy for Multiple Myeloma. Bone Marrow Transplantation, 2007; 39,695-703.
Meehan KR, Wu J, Ernstoff MS, Webber S, Szczepiorkowski ZM, Barber A, Sentman C. Development of a Laboratory Model for Ex Vivo Expansion of Multiple Populations of Effector T Cells. Cytotherapy 2008, 10:30-37.
Schwaab T, Meehan KR, Fadul C, Fisher J, Seigne J, Heaney J, Givan A, Ernstoff E. Dye Dilution Proliferation Assay: Application of the DDPA to Identify Tumor-Specific T Cell Precursor Frequencies in Clinical Trials. Immunological Investigations, 36:1-16, 2007
Barber A, Zhang T, Megli CJ, Meehan KR, Sentman CL. Chimeric NKG2D receptor-expressing T cells as a novel immunotherapy for multiple myeloma. Experimental Hematology 2008; 36:1318-1328.
Huarte E, Fisher J, Turk MJ, Mellinger D, Foster C, Wolf B, Meehan KR, Fadul CE, Ernstoff MS. Ex Vivo Expansion of lymphocytes with IL-15 and IL-21 for Adoptive Immunotherapy in Melanoma. Cancer Letters 2009; 285(1): 80-88.
Gunturu KS, Meehan KR, Mackenzie T, Crocenzi TS, Underwood E, Noelle R, Ernstoff MS, Lymphodepletion with High-Dose Interleukin-2 and GM-CSF in Metastatic Melanoma Patients: A Preliminary Report. Journal of Clinical Oncology 2010, 28(7):1196-202.
Meehan KR, Talebian L, Wu J, Hill, J, Szczepiorkowski Z, Sentman C, Ernstoff MS. Immune Mobilization of Autologous Blood Progenitor Cells: Direct Influence on the Cellular Subsets Collected. Submitted Cytotherapy, March 2010.
Barber A, Meehan KR, Sentman CL. Chimeric NKG2D T cells increase survival and induce protective immunity in a mouse model of myeloma. Submitted. Clin Cancer Research, April 2010.
Relevant Grant Submissions
Results from this COBRE-sponsored project were used in multiple grant submissions, including proposals submitted to the Multiple Myeloma Research Foundation, the V Foundation, and the NIH (R01 proposal).