Theme 5: Antibody and T-cell therapeutics
Overview: Several CCIR members are developing antibody and T cell therapies for different types of cancer and finding ways to improve their efficacy. Much progress has been made recently in the clinical use of antibodies and T cells for cancer therapeutics. Antibodies that target immune checkpoints have been effective in patients with metastatic cancer, and one of these, anti-CTLA-4, pioneered by Dr. James Allison, a new member of the CCIR, has been FDA approved for the treatment of metastatic melanoma. Dr. Allison’s work has opened a new field of utilizing antibodies against immune checkpoints, and other similar antibodies, such as anti-PD1 antibody, have been found to be effective against melanoma as well as renal cancer and lung cancer in patients with metastatic disease. In addition, antibodies that block regulatory immune cell function or activate co-stimulatory molecules, such as anti-OX40, have significant promise. Another modality that has shown significant promise in the clinic is the adoptive transfer of activated T cells. This therapy has been effective in patients with metastatic melanoma, and with genetic engineering using chimeric antigen receptor genes (CAR), T cells can be armed to attack other common cancers, such as leukemias and lymphoma. Clinical development of reagents or strategies as a form of immunotherapy and advancement of cancer immunotherapies are ongoing.
Some highlights from the past year include:
• A phase 2 clinical study, completed at the MD Anderson Cancer Center, showed that the combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma, suggesting that immune checkpoint blockade is worthy of further study in follicular lymphoma (Westin JR, Lancet Oncol. 2014)
• Treatment of patient-derived chemotherapy-resistant acute myelogenous leukemia with a novel T cell receptor-like mAb to PR1/HLA-A2, developed by CCIR investigators, eliminated leukemia stem cells in a xenograft model (Sergeeva A, In Press, 2014)
• A preclinical study found that adoptive T-cell transfer (ACT) with melanoma-specific T cells was much more effective in the context of concurrent BRAF inhibition, which led to increased T-cell infiltration of tumors that could be attributed largely to decreased VEGF production by the tumor cells (Liu CW, Clin Cancer Res. 2012)
Additional Relevant Publications:
- Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, Yagita H, Overwijk WW, Lizée G, Radvanyi L, Hwu P. PD-1 Blockade Enhances T-cell Migration to Tumors by Elevating IFN-γ Inducible Chemokines. Cancer Res. 2012, 72(20):5209-18.
- Zhang M, Maiti S, Bernatchez C, Huls H, Rabinovich B, Champlin RE, Vence LM, Hwu P, Radvanyi L, Cooper LJ. A new approach to simultaneously quantify both TCR α- and β-chain diversity after adoptive immunotherapy. Clin Cancer Res. 2012, 18(17):4733-42.
- Torikai H, Reik A, Liu PQ, Zhou Y, Zhang L, Maiti S, Huls H, Miller JC, Kebriaei P, Rabinovitch B, Lee DA, Champlin RE, Bonini C, Naldini L, Rebar EJ, Gregory PD, Holmes MC, Cooper LJ. A foundation for universal T cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood. 2012, 119(24):5697-705.
- Liu C, Lewis CM, Lou Y, Xu C, Peng W, Yang Y, Gelbard AH, Lizee G, Zhou D, Overwijk WW, Hwu P. Agonistic antibody to CD40 boosts the antitumor activity of adoptively transferred T cells in vivo. J Immunother. 2012, 35(3):276-82.
- O'Connor CM, Sheppard S, Hartline CA, Huls H, Johnson M, Palla SL, Maiti S, Ma W, Davis RE, Craig S, Lee DA, Champlin R, Wilson H, Cooper LJ. Adoptive T cell therapy improves treatment of canine non-Hodgkin lymphoma post chemotherapy. Sci Rep. 2012, 2:249.
- Denman CJ, Senyukov VV, Somanchi SS, Phatarpekar PV, Kopp LM, Johnson JL, Singh H, Hurton L, Maiti SN, Huls MH, Champlin RE, Cooper LJ, Lee DA. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS One. 2012, 7(1):e30264.
- Kebriaei P, Huls H, Jena B, Munsell M, Jackson R, Lee DA, Hackett PB, Rondon G, Shpall E, Champlin RE, Cooper LJ. Infusing CD19-directed T cells to augment disease control in patients undergoing autologous hematopoietic stem-cell transplantation for advanced B-lymphoid malignancies. Hum Gene Ther. 2012, 23(5):444-50.
- Roszik J, Rabinovich B, Cooper LJ. Imaging of T cells expressing chimeric antigen receptors. Immunotherapy. 2011, 3(12):1411-4.
- Huang G, Yu L, Cooper LJ, Hollomon M, Huls H, Kleinerman ES. Genetically modified T cells targeting interleukin-11 receptor a-chain kill human osteosarcoma cells and induce the regression of established osteosarcoma lung metastases. Cancer Res. 2012, 72(1):271-81. .
- Joseph RW, Peddareddigari VR, Liu P, Miller PW, Overwijk WW, Bekele NB, Ross MI, Lee JE, Gershenwald JE, Lucci A, Prieto VG, McMannis JD, Papadopoulos N, Kim K, Homsi J, Bedikian A, Hwu WJ, Hwu P, Radvanyi LG. Impact of clinical and pathologic features on tumor-infiltrating lymphocyte expansion from surgically excised melanoma metastases for adoptive T cell therapy. Clin Cancer Res. 2011, 17(14):4882-91.
- Singh H, Figliola MJ, Dawson MJ, Huls H, Olivares S, Switzer K, Mi T, Maiti S, Kebriaei P, Lee DA, Champlin RE, Cooper LJ. Reprogramming CD19-specific T cells with IL-21 signaling can improve adoptive immunotherapy of B-lineage malignancies. Cancer Res. 2011, 71(10):3516-27.
- Cao Y, Lan Y, Qian J, Zheng Y, Hong S, Li H, Wang M, Kwak LW, Lin D, Yang J, Yi Q. Targeting cell surface β2-microglobulin by pentameric IgM antibodies. Br J Haematol. 2011, 154(1):111-21.
- Jin Z, Maiti S, Huls H, Singh H, Olivares S, Mates L, Izsvak Z, Ivics Z, Lee DA, Champlin RE, Cooper LJ. The hyperactive Sleeping Beauty transposase SB100X improves the genetic modification of T cells to express a chimeric antigen receptor. Gene Ther. 2011, 18(9):849-56.
- Hernandez-Chacon JA, Li Y, Wu RC, Bernatchez C, Wang Y, Weber JS, Hwu P, Radvanyi LG. Costimulation through the CD137/4-1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances antitumor effector function. J Immunother. 2011, 34(3):236-50.
- Sergeeva A, Alatrash G, He H, Ruisaard K, Lu S, Wygant J, McIntyre BW, Ma Q, Li D, St John L, Clise-Dwyer K, Molldrem JJ. An anti-PR1/HLA-A2 T cell receptor-like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells. Blood. 2011, 117(16):4262-72.
- Li D, Li Y, Hernandez JA, Patenia R, Kim TK, Khalili J, Dougherty MC, Hanley PJ, Bollard CM, Komanduri KV, Hwu P, Champlin RE, Radvanyi LG, Molldrem JJ, Ma Q. Lovastatin inhibits T cell proliferation while preserving the cytolytic function of EBV, CMV, and MART-1-specific CTLs. J Immunother. 2010, 33(9):975-82.
- Peng W, Ye Y, Rabinovich BA, Liu C, Lou Y, Zhang M, Whittington M, Yang Y, Overwijk WW, Lizée G, Hwu P. Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses. Clin Cancer Res. 2010, 16(22):5458-68.
- Ma Q, Wang C, Jones D, Quintanilla KE, Li D, Wang Y, Wieder ED, Clise-Dwyer K, Alatrash G, Mj Y, Munsell MF, Lu S, Qazilbash MH, Molldrem JJ. Adoptive transfer of PR1 cytotoxic T lymphocytes associated with reduced leukemia burden in a mouse acute myeloid leukemia xenograft model. Cytotherapy. 2010, 12(8):1056-62.
- Kanodia S, Wieder E, Lu S, Talpaz M, Alatrash G, Clise-Dwyer K, Molldrem JJ. PR1-specific T cells are associated with unmaintained cytogenetic remission of chronic myelogenous leukemia after interferon withdrawal. PLoS One. 2010, 5(7):e11770.
- Choi Y, Yuen C, Maiti SN, Olivares S, Gibbons H, Huls H, Raphael R, Killian TC, Stark DJ, Lee DA, Torikai H, Monticello D, Kelly SS, Kebriaei P, Champlin RE, Biswal SL, Cooper LJ. A high throughput microelectroporation device to introduce a chimeric antigen receptor to redirect the specificity of human T cells. Biomed Microdevices. 2010, 12(5):855-63.
- Davies JK, Singh H, Huls H, Yuk D, Lee DA, Kebriaei P, Champlin RE, Nadler LM, Guinan EC, Cooper LJ. Combining CD19 redirection and alloanergization to generate tumor-specific human T cells for allogeneic cell therapy of B-cell malignancies. Cancer Res. 2010, 70(10):3915-24.
- Liu S, Etto T, Rodriguez-Cruz T, Li Y, Wu C, Fulbright OJ, Hwu P, Radvanyi L, Lizée G. TGF-beta1 induces preferential rapid expansion and persistence of tumor antigen-specific CD8+ T cells for adoptive immunotherapy. J Immunother. 2010, 33(4):371-81.
- Hurton LV, Siddik RI, Singh H, Olivares S, Rabinovich BA, Tian R, Mojsilovic D, Hildebrand W, Lee DA, Kelly SS, Champlin R, Shpall EJ, Fernandez-Viña M, Cooper LJ. Identifying candidate allogeneic NK-cell donors for hematopoieticstem-cell transplantation based on functional phenotype. Leukemia. 2010, 24(5):1059-62.
- Li Y, Liu S, Hernandez J, Vence L, Hwu P, Radvanyi L. MART-1-specific melanoma tumor-infiltrating lymphocytes maintaining CD28 expression have improved survival and expansion capability following antigenic restimulation in vitro. J Immunol. 2010, 184(1):452-65.
- Manuri PV, Wilson MH, Maiti SN, Mi T, Singh H, Olivares S, Dawson MJ, Huls H, Lee DA, Rao PH, Kaminski JM, Nakazawa Y, Gottschalk S, Kebriaei P, Shpall EJ, Champlin RE, Cooper LJ. piggyBac transposon/transposase system to generate CD19-specific T cells for the treatment of B-lineage malignancies. Hum Gene Ther. 2010, 21(4):427-37. .
- Yang J, Cao Y, Hong S, Li H, Qian J, Kwak LW, Yi Q. Human-like mouse models for testing the efficacy and safety of anti-beta2-microglobulin monoclonal antibodies to treat myeloma. Clin Cancer Res. 2009, 15(3):951-9.
- Singh H, Najjar AM, Olivares S, Nishii R, Mukhopadhyay U, Alauddin M, Manuri PR, Huls H, Lee DA, Dotti G, Bollard C, Simmons PJ, Shpall EJ, Champlin RE,Gelovani JG, Cooper LJ. PET imaging of T cells derived from umbilical cord blood. Leukemia. 2009, 23(3):620-2.
- Voorhees PM, Chen Q, Small GW, Kuhn DJ, Hunsucker SA, Nemeth JA, Orlowski RZ. Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death. Br J Haematol. 2009, 145(4): 481-90.
- Wang M, Sun L, Qian J, Han X, Zhang L, Lin P, Cai Z, Yi Q. Cyclin D1 as a universally expressed mantle cell lymphoma-associated tumor antigen for immunotherapy. Leukemia. 2009, 23(7): 1320-8.
- Wang Y, Li D, Jones D, Bassett R, Sale GE, Khalili J, Komanduri KV, Couriel DR, Champlin RE, Molldrem JJ, Ma Q. Blocking LFA-1 activation with lovastatin prevents graft-versus-host disease in mouse bone marrow transplantation. Biol Blood Marrow Transplant. 2009, 5(12): 1513-22.
- Rabinovich BA, Ye Y, Etto T, Chen JQ, Levitsky HI, Overwijk WW, Cooper LJ, Gelovani J, Hwu P. Visualizing fewer than 10 mouse T cells with an enhanced firefly luciferase in immunocompetent mouse models of cancer. Proc Natl Acad Sci U S A. 2008, 105(38):14342-6.
- Singh H, Manuri PR, Olivares S, Dara N, Dawson MJ, Huls H, Hackett PB, Kohn DB, Shpall EJ, Champlin RE, Cooper LJ. Redirecting specificity of T cell populations for CD19 using the Sleeping Beauty system. Cancer Res. 2008, 68(8):2961-71.
- Lee ST, Liu S, Radvanyi L, Sukhumalchandra P, Molldrem JJ, Wieder ED, Hwu P, Liu YJ, Kwak LW, Lizee G, Neelapu SS. A novel strategy for rapid and efficient isolation of human tumor-specific CD4(+) and CD8(+) T cell clones. J Immunol Methods. 2008, 331(1-2):13-26.