A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer

Purpose: A phase I study was conducted to assess the safety of adoptive immunotherapy using gene-modified autologous T cells for the treatment of metastatic ovarian cancer. Experimental Design: T cells with reactivity against the ovarian cancer–associated antigen α-folate receptor (FR) were generated by genetic modification of autologous T cells with a chimeric gene incorporating an anti-FR single-chain antibody linked to the signaling domain of the Fc receptor γ chain. Patients were assigned to one of two cohorts in the study. Eight patients in cohort 1 received a dose escalation of T cells in combination with high-dose interleukin-2, and six patients in cohort 2 received dual-specific T cells (reactive with both FR and allogeneic cells) followed by immunization with allogeneic peripheral blood mononuclear cells. Results: Five patients in cohort 1 experienced some grade 3 to 4 treatment-related toxicity that was probably due to interleukin-2 administration, which could be managed using standard measures. Patients in cohort 2 experienced relatively mild side effects with grade 1 to 2 symptoms. No reduction in tumor burden was seen in any patient. Tracking 111In-labeled adoptively transferred T cells in cohort 1 revealed a lack of specific localization of T cells to tumor except in one patient where some signal was detected in a peritoneal deposit. PCR analysis showed that gene-modified T cells were present in the circulation in large numbers for the first 2 days after transfer, but these quickly declined to be barely detectable 1 month later in most patients. An inhibitory factor developed in the serum of three of six patients tested over the period of treatment, which significantly reduced the ability of gene-modified T cells to respond against FR+ tumor cells. Conclusions: Large numbers of gene-modified tumor-reactive T cells can be safely given to patients, but these cells do not persist in large numbers long term. Future studies need to employ strategies to extend T cell persistence. This report is the first to document the use of genetically redirected T cells for the treatment of ovarian cancer.

[1]  A. Boynton,et al.  Anti‐prostate specific membrane antigen designer T cells for prostate cancer therapy , 2004, The Prostate.

[2]  Sanjiv S Gambhir,et al.  Quantitative imaging of the T cell antitumor response by positron-emission tomography , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[3]  S. Rosenberg,et al.  Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. , 2005, The Journal of clinical investigation.

[4]  A. Thor,et al.  Distribution of oncofetal antigen tumor-associated glycoprotein-72 defined by monoclonal antibody B72.3. , 1986, Cancer research.

[5]  Douglas D. Taylor,et al.  Modulation of CD3-zeta as a marker of clinical response to IL-2 therapy in ovarian cancer patients. , 2004, Gynecologic oncology.

[6]  J. Mcarthur,et al.  Anti-Tumor CC49-ζ CD4 T Cells Possess Both Cytolytic and Helper Functions , 2000 .

[7]  M. Smyth,et al.  Supernatural T cells: genetic modification of T cells for cancer therapy , 2005, Nature Reviews Immunology.

[8]  J. Blattman,et al.  Adoptive immunotherapy: engineering T cell responses as biologic weapons for tumor mass destruction. , 2003, Cancer cell.

[9]  S. Rosenberg,et al.  In vivo distribution of adoptively transferred indium-111-labeled tumor infiltrating lymphocytes and peripheral blood lymphocytes in patients with metastatic melanoma. , 1989, Journal of the National Cancer Institute.

[10]  S. Rosenberg,et al.  Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain , 1993, The Journal of experimental medicine.

[11]  Michel Sadelain,et al.  Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ /CD28 receptor , 2002, Nature Biotechnology.

[12]  V. Zurawski,et al.  Cloning of a tumor-associated antigen: MOv18 and MOv19 antibodies recognize a folate-binding protein. , 1991, Cancer research.

[13]  S. Rosenberg,et al.  Expansion and characterization of T cells transduced with a chimeric receptor against ovarian cancer. , 2000, Human gene therapy.

[14]  S. Canevari,et al.  Level of anti‐mouse‐antibody response induced by bi‐specific monoclonal antibody OC/TR in ovarian‐carcinoma patients is associated with longer survival , 1999, International journal of cancer.

[15]  Michel Sadelain,et al.  Targeted elimination of prostate cancer by genetically directed human T lymphocytes. , 2005, Cancer research.

[16]  J. da Silva,et al.  Characterization of a human ovarian adenocarcinoma line, IGROV1, in tissue culture and in nude mice. , 1985, Cancer research.

[17]  Nicola Ragni,et al.  HER2/neu Oncoprotein Overexpression in Epithelial Ovarian Cancer: Evaluation of its Prevalence and Prognostic Significance , 2005, Oncology.

[18]  S. Ménard,et al.  Folate binding protein distribution in normal tissues and biological fluids from ovarian carcinoma patients as detected by the monoclonal antibodies MOv18 and MOv19. , 1994, European journal of cancer.

[19]  M. Brenner,et al.  Genetic modification of T lymphocytes for adoptive immunotherapy. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[20]  S. Rosenberg,et al.  Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  P. Hwu,et al.  Dual-specific T cells combine proliferation and antitumor activity , 2002, Nature Biotechnology.

[22]  S. Steinberg,et al.  Localization of 111Indium‐labeled tumor infiltrating lymphocytes to tumor in patients receiving adoptive immunotherapy. Augmentation with cyclophosphamide and correlation with response , 1994, Cancer.

[23]  Z. Eshhar,et al.  Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes. , 2004, The Journal of clinical investigation.

[24]  S. Ménard,et al.  Characterization of human ovarian carcinoma‐associated antigens defined by novel monoclonal antibodies with tumor‐restricted specificity , 1987, International journal of cancer.

[25]  B. Yin,et al.  Serological and immunochemical analysis of Lewis Y (Ley) blood group antigen expression in epithelial ovarian cancer , 1996, International journal of cancer.

[26]  R. Freedman,et al.  Immunotherapy for peritoneal ovarian carcinoma metastasis using ex vivo expanded tumor infiltrating lymphocytes. , 1996, Cancer treatment and research.

[27]  S. Rosenberg,et al.  In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes. , 1995, Cancer research.

[28]  S. Ménard,et al.  Evaluation of the immunoreactive fraction of an anti-tumour monoclonal antibody. , 1990, The British journal of cancer. Supplement.

[29]  J. Mcarthur,et al.  Anti-Tumor CC49-zeta CD4 T cells possess both cytolytic and helper functions. , 2000, Journal of immunotherapy.

[30]  F. Thistlethwaite,et al.  Engineering T cells for cancer therapy , 2005, British Journal of Cancer.

[31]  S. Canevari,et al.  Panning phage antibody libraries on cells: isolation of human Fab fragments against ovarian carcinoma using guided selection. , 1998, Cancer research.

[32]  J. Trapani,et al.  Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors. , 2002, Blood.

[33]  J. Trapani,et al.  Rejection of Syngeneic Colon Carcinoma by CTLs Expressing Single-Chain Antibody Receptors Codelivering CD28 Costimulation , 2003, The Journal of Immunology.

[34]  S. Forman,et al.  Specific Recognition and Killing of Glioblastoma Multiforme by Interleukin 13-Zetakine Redirected Cytolytic T Cells , 2004, Cancer Research.

[35]  S. Rosenberg,et al.  A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. , 1986, Science.