Department of Microbiology and Immunology
Our laboratory focuses on developing novel T-cell immunotherapies for patients with advanced cancer. Our strategy is based on the use of mouse models to develop human clinical trials that effectively harness the patient’s own immune system to kill cancer.
We study new ways to improve adoptive cell transfer (ACT) therapy, which involves removal of T cells from the patient, their expansion/manipulation ex-vivo, followed by their return to patient preconditioned with lymphodepletion via chemotherapy agents and/or total body irradiation.
Lymphodepletion significantly enhances the efficacy of ACT therapies. However, host conditioning with lymphodepletion is not the only factor that positively impacts clinical outcome. We and other investigators have found that the functional properties of T cells are critical for successful tumor immunotherapy.
We have very recently found that CD4 and CD8 T cells that produce IL-17 (Th17 and Tc17 cells, respectively) mediate robust tumor regression. Additional investigation revealed that the expansion of Th17/Tc17 cells with the costimulatory molecule ICOS but not CD28 further improved their function and their ability to eradiate large tumors (see Fig1). Although ICOS-expanded Th17/Tc17 cells mediate potent tumor regression, the cellular, biochemical and molecular mechanisms underlying how ICOS signaling drives the differentiation and expansion of cells that produce high levels of IL-17, IL-21 and IFN-gamma compared to those stimulated with CD28 remains incompletely elucidated. Thus, we are now investigating key transcription factors regulated by ICOS versus CD28 that distinctly impact their functional fate. We are also investigating the mechanism governing the in vivo effectiveness of ICOS-expanded tumor-specific Tc17/Th17 cells using the clinically relevant transgenic ACT mouse models of cancer created in Dr. Nicholas Restifo’s laboratory.
In summary, research in the Paulos laboratory will focus on broadening the utility and efficacy of the ACT approach. We are particularly interested in improving host preconditioning regimens as well as augmenting various T-cell subsets by ex-vivo and in-vivo manipulation with novel cytokine/chemical cocktails and with ICOS agonists (as well as with other costimulatory molecules). We believe that our investigations will provide vital information on how to build on the next generation of T-cell based immunotherapies for cancer as well as for autoimmunity and infectious diseases.
Recent Publications | Additional Publications
*denotes shared first author
C.M. Paulos, C. Carpenito, G. Plesa, T.N. Golovina, R. Carroll, J.L. Riley, C.H. June. ICOS critically regulates the expansion and function of inflammatory human Th17 cells. Science TM 2(55):55ra78 (2010). *Accompanying Perspective and Science Highlight.
C.M. Paulos and C.H. June. Putting the brakes on BTLA expression for T-cell mediated cancer immunotherapy. J Clin Invest 120(1):76-80 (2010).
*C. Wrzesinski, C.M. Paulos, A. Kaiser, P. Muranski, D.C. Palmer, L. Gattinoni, Z. Yu, S.A. Rosenberg, N.P Restifo. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J Immunother 33(1):1-7 (2010).
L. Gattinoni, X.S. Zhong, D.C. Palmer, Y. Ji, C.S. Hinrichs, Z. Yu, C. Wrzesinski, A. Boni, L. Cassard, L.M. Garvin, C.M. Paulos, P. Muranski, N.P. Restifo. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med 15(7):808-813 (2009).
*C.S. Hinrichs, A. Kaiser, C.M. Paulos, L Cassard, L Sanchez-Perez, B. Heemskerk, C. Wrzesinski, Z.A Borman, P. Muranski, N.P. Restifo. Type 17 CD8+ T cells display enhanced anti-tumor immunity. Blood 114(3):596-9 (2009).
C.M. Paulos, M.M. Suhoski, G. Plesa, T. Jiang, S Basu, T.N. Golovina, S. Jiang, N.A. Aqui, D.J. Jr Powell, B.L. Levine, R.G. Carroll, J.L. Riley, C.H. June. Adoptive immunotherapy: good habits instilled at youth have long-term benefits. Immunol Res 42(1-3):182-96 (2008).
P. Muranski, A. Boni, P.A. Antony, L. Cassard, K.R. Irvine, A. Kaiser, C.M. Paulos, D.C. Palmer, C.E. Touloukian, K. Ptak, L. Gattinoni, C. Wrzesinski, C.S. Hinrichs, C. Chan, N.P. Restifo. Tumor-specific Th17 cells eradiate large established melanoma. Blood 112(2):32-73 (2008).
D.C. Palmer, C. Chan, L. Gattinoni, C. Wrzesinski, C.M. Paulos, C.S. Hinrichs, D.J. Powell Jr. Z. Yu, C.A. Klebanoff, S.E. Finkelstein, R.N. Fariss, M.E. Dudley, R.B. Nussenblatt, S.A. Rosenberg, N.P. Restifo. Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity. Proc Natl Acad Sci 105(23):8061-6 (2008).
C.S. Hinrichs, R. Spolski, C.M. Paulos, L. Gattinoni, K.W. Kerstann, D.C. Palmer, C.A. Klebanoff, S.A. Rosenberg, W.J. Leonard, N.P. Restifo. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood 111(11):5326-33 (2008).
C.M. Paulos, A. Kaiser, C. Wrzesinski, C.S. Hinrichs, L. Cassard, D.C. Palmer, A. Boni, P. Muranski, Z. Yu, P.A. Antony, L. Gattinoni, S.A. Rosenberg, N.P. Restifo. Toll-like receptors in tumor immunotherapy. Clin Cancer Res 13(18 pt.1):5280-9 (2007).
C.M. Paulos, C. Wrzesinski, A. Kaiser, C.S. Hinrichs, M. Chieppa, L. Cassard, D.C. Palmer, A. Boni, P. Muranski, Z. Yu, L. Gattinoni, P.A. Antony, S.A. Rosenberg, N.P. Restifo. Microbial translocation augments the function of self/tumor-specific CD8+ T cells via TLR4 signaling. J Clin Invest 117(8):2197-204 (2007).
C. Wrzesinski, C.M. Paulos, L. Gattinoni, D.C. Palmer, A. Kaiser, Z. Yu, S.A. Rosenberg, N.P. Restifo. Hematopoitic stem cells promote the expansion and function of adoptively transferred antitumor CD8+ T cells. J Clin Invest 117(2):492-501 (2007).
P.A. Antony, C.M. Paulos, M. Ahmadzadeh, A. Akpinarli, D.C. Palmer, N. Sato, A. Kaiser, C.S. Hinrichs, C.A. Klebanoff, Y. Tagaya, N.P. Restifo. IL-2 dependent mechanisms of tolerance and immunity in vivo. J Immunol 176(9):5255-66 (2006).