Thomas Gajewski, M.D., Ph.D.

Regulation of T-cell Activation, T-cell Signaling, Tumor Immunology, Immunotherapy of Melanoma

Research Summary

Our laboratory studies the molecular and cellular regulation of T lymphocyte activation and differentiation, and in turn applies this information to preclinical and clinical efforts to promote anti-tumor immunity in vivo.

T Lymphocyte Biology

Naive T cells that have never seen antigen lack effector function and must acquire such functions through a differentiation process. Initial activation depends on engagement of the T cell receptor (TCR) as well as additional receptor/ligation interactions that influence the quantity and quality of the T cell response. Positive regulatory influences include CD28 engagement by B7, and negative regulatory processes include ligation of CTLA4 or by induction of an unresponsive state termed anergy. In addition to this quantitative level of control, T cell activation is also qualitatively influenced by exogenous cytokines that promote differentiation down distinct lineages of effector cell phenotype having specialized functions. We study the molecular and biochemical events that mediate regulation of T cells in the naive, effector, and anergic states, as well as the process of transitioning from one state to another. These experiments rely upon mutagenesis and viral transduction techniques, transgenic and knockout mice, and a variety of cellular immunology approaches.

Regulation of Anti-tumor Immunity

Recent work has suggested that most tumors express antigens that can be recognized as foreign by specific T cells. How and why tumors than grow and escape immune destruction has become a central problem in cancer biology. We hypothesize that part of the defect may be due to inappropriate T cell differentiation or the dominant effects of negative regulatory influences on T cell activation. In order to determine the factors necessary for tumor rejection when it successfully occurs, we study the rejection of immunogenic tumors in knockout mice lacking individual molecules expected to affect specific aspects of T cell activation and differentiation. To examine which factors are sufficient to induce anti-tumor immunity, we supply these factors in antigen-specific vaccination strategies to promote rejection of established tumors in mice. Successful preclinical tumor vaccine results are then applied to clinical trials in the melanoma clinic which I also direct. Other immunologic manipulations are explored in our clinical cancer immunotherapy group.

Selected Papers

Fields P, Gajewski TF, and Fitch FW. (1996). Blocked Ras activation in anergic CD4+ T cells. Science, 271:1276-1278.

Fallarino F, Fields PE, and Gajewski TF. (1998). B7-1 engagement of CTLA4 inhibits T cell activation in the absence of CD28. J. Exp. Med., 188:205-210.

Bird JJ, Brown DR, Mullen AC, Moskowitz NH, Gajewski TF, Wang C-R, and Reiner SL. (1998). Helper T cell differentiation is controlled by the cell cycle. Immunity, 9:229-237.

Wan YY, Leon RP, Marks R, Cham CM, Schaack J, Gajewski TF, and DeGregori J. (2000). Transgenic expression of the coxsackie/adenovirus receptor (CAR) enables adenoviral mediated gene delivery in naive T cells. Proc.Natl.Acad.Sci.USA., 97:13784-13789.

Fallarino F, Uyttenhove C, Boon T, and Gajewski TF. (1999). Improved efficacy of dendritic cell vaccines, and successful immunization with tumor antigen peptide-pulsed PBMC, by co-administration of rmIL-12. Int. J. Cancer., 80:324-333.

Fallarino F and Gajewski TF. (1999). Cutting Edge: Differentiation of anti-tumor CTL in vivo requires host expression of Stat1. J. Immunol. 163:4109-4113.

Kacha AK, Fallarino F, Markiewicz MA and Gajewski TF. (2000). Cutting Edge: Spontaneous rejection of poorly immunogenic P1.HTR tumors by Stat6-deficient mice. J. Immunol. 165:6024-6028.

Wan YY, Leon RP, Marks R, Cham CM, Schaack J, Gajewski TF and DeGregori J. (2000). Transgenic expression of the coxsackie/adenovirus receptor (CAR) enables adenoviral mediated gene delivery in naive T cells. Proc. Natl. Acad. Sci. USA. 97:13784-13789.

Gajewski TF, Fallarino F, Fields PE, Rivas F and Alegre ML. (2001). Absence of CTLA-4 lowers the activation threshold of primed CD8+ TCR transgenic T cells: Lack of correlation with SHP2. J. Immunol. 166:3900-3907.

Gajewski TF, Fallarino F, Ashikari A and Sherman ML. (2001). Immunization of HLA-A2+ melanoma patients with MAGE-3 or MelanA peptide-pulsed autologous PBMC plus rhIL-12. Clin. Cancer Res. 7:895-901.

Markiewicz MA, Fallarino F, Ashikari A and Gajewski TF. (2001). Epitope spreading upon tumor rejection triggered by immunization with a single class I MHC-binding peptide. Int. Immunol. 13:625-632.

Rivas FV, O'Herrin S and Gajewski TF. (2001). CD28 is not required for JNK activation in T cells. J. Immunol. 167:3123-3128.

Rini BI, Zimmerman T, Stadler WM, Gajewski TF and Vogelzang NJ. (2002). Allogeneic stem cell transplantation of renal cell cancer after non-myeloablative chemotherapy: Feasibility, engraftment and clinical results. J. Clin. Oncol. 20:2017-2024.

Rivas F, Alegre M, O'Keefe J and Gajewski TF. (2004). The actin cytoskeleton regulates calcium dynamics and NFAT nuclear duration. Mol. Cell. Biol. 24:1628.

Harlin H, Artz A, Mahowald M, Zimmerman T, Rini BI, Vogelzang NJ and Gajewski TF. (2004). Clinical responses following non-myeloablative allogeneic stem cell transplantation for kidney cancer correlate with expansion of CD8+ IFN-g-producing T cells. Bone Marrow Trans. 33:491.

Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T and Gajewski TF. (2004). PD-L1 inhibits the effector phase of tumor rejection by TCR transgenic CD8+ T cells. Cancer Res. 64:1140.

Medved M, Karczmar G, Yang C, Dignam J, Gajewski TF, Kindler H, Vokes E, MacEneany P and Stadler W. (2004). Semi-quantitative analysis of dynamic contrast enhanced MRI in cancer patients: Variability and changes in tissue over time. JMRI. 20:122.

Peterson A, Stadler W and Gajewski TF. (2004). Phase II study of the Flk-1 tyrosine kinase inhibitor SU5416 in metastatic melanoma. Clin. Can. Res. 10:4048.

Aklilu M, George C, Stadler W, Markiewicz M, Vogelzang N, Mahowald M, Johnson M and Gajewski TF. (2004). Depletion of normal B cells with Rituximab as an adjunct to IL-2 therapy for renal cell carcinoma and melanoma. Annals Oncol. 15:1109.

O'Keefe J, Blaine K, Alegre M and Gajewski TF. (2004). cSMAC formation is not required for activation of naive CD8+ T cells. Proc. Natl. Acad. Sci. 101:9351.

Artz AS, VanBesien K, Zimmerman T, Gajewski TF, Rini BI, Hu HS, Stadler WM and Vogelzang NJ. (2004). Long-term follow up of non-myeloablative allogeneic stem cell transplantation for renal cell carcinoma: The University of Chicago experience. Bone Marrow Trans.

Zimmerman T, Harlin H, Odenike T, Berk S, Sprague E, Karrison T, Stock W, Larson RA, Ratain MJ and Gajewski TF. (2004). A dose-ranging pharmacodynamic study of R115777 (tipfarnib) in patients with relapsed and refractory hematologic malignancies. J. Clin. Oncol. 22:4764.

Gajewski TF. (2004). Temozolomide for melanoma: new toxicities and new opportunities. Editorial, J. Clin. Onc. 22:580.

Gajewski TF. (2004). Update on vaccines for solid tumors. Clinical Advances in Hematology and Oncology. 2:158.

Zha Y, Blank C and Gajewski TF. (2004). Negative regulation of T cell function by PD-1. Critical Reviews in Immunology. 24:229.