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Department of Surgery

Mark Rubinstein, PhD

My research group is focused on four broad areas:

Mark Rubinstein, PhD

1)  Developing enhanced T cell-based therapeutics for the treatment of cancer.  Probably the most promising therapeutic approach to treat patients with metastatic cancer is adoptive T cell therapy.  In select cancers, this therapy can cure patients that would otherwise have no hope.   However, most cancers are not currently amenable to immune-based therapy, and even in amenable cancers, only a subset of patients have significant responses.  To make adoptive T cell therapy more broadly applicable, my laboratory is working on several novel approaches including: 1) developing improved polarization and culture conditions for T cells prior to adoptive T cell transfer, 2) using gene transfer techniques to enhance the therapeutic efficacy of T cells, and 3) using cytokine-based therapeutics to augment the response of T cells after adoptive transfer.  As a member of the MUSC immunotherapy translational group, we are also working to translate our most effective approaches into the clinic.

2)  Studying basic lymphocyte biology.    A second major effort in the laboratory is to understand how extracellular signals regulate T cells and other immune cell subsets.  For example, what are the cytokine requirements for mature lymphocyte survival and function?  How do IL-2 and IL-15 mediate differential signaling under psychological conditions?   And what are the role of costimulatory and inhibitory molecules in driving T cell responses?  In answering these and related questions, our goal is to develop novel therapies for the treatment of cancer and infectious disease.

3)  Creating novel protein therapeutics.  The biological activity of many proteins, especially cytokines, is limited by poor half-life and target cell specificity.  Using soluble receptors and antibodies, as well as other approaches, we are developing methods to make proteins (such as IL-2 or IL-15) more therapeutically efficacious against cancer and other diseases.  As one example, we have discovered that the biological activity of IL-15, a promising anti-cancer therapeutic, can be enhanced 100-fold in vivo by pre-association with its soluble IL-15Rα. This reagent, which we call IL-15 complexes, can potently enhance the function of adoptively transferred tumor-reactive T cells.   This represents one approach we are taking to create novel molecules both as tools to study lymphocyte biology and for therapeutic application.

4)  Understanding tumor-induced immune suppression.  One problem in applying immune-based approaches for the treatment of cancer is that the tumor cells often suppress immune responses.  Thus, inducing an effective immune response may require either reversing suppression or making immune cells resistant to suppression. As one example of our ongoing research, we are collaborating with physicians and assessing whether T cells from breast cancer patients are dysfunctional as a result of tumor progression. Ultimately, we hope to apply our findings to developing more effective adjuvant strategies for tumor immunotherapy.

Selected publications:

  1. Rubinstein MP, Cloud CA, Garrett TE, Moore CJ, Schwartz KM, Johnson CB, Craig DH, Salem ML, Paulos CM, Cole DJ. 2012. Ex vivo interleukin-12-priming during CD8(+) T cell activation dramatically improves adoptive T cell transfer antitumor efficacy in a lymphodepleted host. J Am Coll Surg 214: 700-7; discussion 7-8
  2. Cole DJ, Rubinstein MP. 2012. Soluble IL-15/IL-15Ralpha complexes in human serum. Blood 120: 1-2
  3. Elpek KG, Rubinstein MP, Bellemare-Pelletier A, Goldrath AW, Turley SJ. 2010. Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Ralpha complexes. Proc Natl Acad Sci U S A 107: 21647-52
  4. Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG, Coussens LM, Karin M, Goldrath AW, Johnson RS. 2010. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res 70: 7465-75
  5. Rubinstein MP, Salem ML, Kadima AN, Nguyen CL, Gillanders WE, Nishimura MI, Cole DJ. 2009. Loss of T cell-mediated antitumor immunity after construct-specific downregulation of retrovirally encoded T-cell receptor expression in vivo. Cancer Gene Ther 16: 171-83
  6. Rubinstein MP, Lind NA, Purton JF, Filippou P, Best JA, McGhee PA, Surh CD, Goldrath AW. 2008. IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response. Blood 112: 3704-12
  7. Epardaud M, Elpek KG, Rubinstein MP, Yonekura AR, Bellemare-Pelletier A, Bronson R, Hamerman JA, Goldrath AW, Turley SJ. 2008. Interleukin-15/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells. Cancer Res 68: 2972-83
  8. Rubinstein MP, Kovar M, Purton JF, Cho JH, Boyman O, Surh CD, Sprent J. 2006. Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc Natl Acad Sci U S A 103: 9166-71
  9. Boyman O, Kovar M, Rubinstein MP, Surh CD, Sprent J. 2006. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311: 1924-7

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