GENE MODIFIED VACCINE IN COMBINATION WITH IPILIMUMAB FOR ADVANCED PANCREATIC CANC
Daniel A Laheru
Department/ Educational Institution Type:
Grant 5R21CA126058-02 from National Cancer Institute
Abstract: The broad objective of this proposal is to test the hypothesis that there is an association of immunologic responses with clinical responses in patients with metastatic pancreatic adenocarcinoma treated with anti-CTLA-4 (Ipilimumab) alone and in combination with vaccine. This study will assess safety, efficacy, and immune activation in these patients. An irradiated GM-CSF-gene modified allogeneic pancreatic cancer vaccine would provide shared immunodominant tumor antigens that could subsequently recruit and activate tumor specific T cells. The use of this vaccine has been shown to be safe and feasible in the adjuvant setting integrated with chemoradiation. In addition, it has been shown to induce mesothelin-specific T cells in the adjuvant setting and when combined with immune modulating doses of cyclophosphamide in the metastatic setting. One of the obstacles to an effective immune therapy is the induction of immune tolerance to cancer cells. One of the agents under development to modulate immune tolerance is an antibody to cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), which is transiently upregulated on activated T cells and provides an inhibitory signal to T cells undergoing activation. It is also constitutively activated on regulatory T cells (Tregs). This proposal aims to evaluate Ipilimumab in patients with metastatic pancreatic cancer. In addition, we will build on our experience with the gene-modified pancreatic cancer vaccine by combining GM-CSF based vaccines with an antibody to CTLA-4. Patients will be enrolled in groups of 3. We will escalate the treatment through 4 stages Ipilimumab 5mg/kg alone, Ipilimumab 5mg/kg + vaccine, Ipilimumab 10mg/kg alone, and Ipilimumab 10mg/kg + vaccine. Since previous studies have shown an association between toxicity and response, we will consider a toxicity level of <33% to be acceptable. The cohorts of the maximum dose Ipilimumab alone and Ipilimumab + vaccine for which the toxicity is <33% will be expanded in order to refine the estimates of toxicity and efficacy. A 21 randomization schema favoring the combination group will be used to allocate patients up to a total of 33 evaluable patients. The primary objective is to characterize the safety profile and immune responses in patients treated with Ipilimumab alone and Ipilimumab in combination with vaccine. The secondary objectives are to estimate response rate, progression-free survival, and overall survival in each of the study arms separately. This proposal aims to combine Ipilimumab with a pancreatic cancer vaccine in patients with metastatic disease. Ipilimumab is an agent that may enhance the body´s immune response to the vaccine and ultimately to the cancer
Keywords: 1-(2-Oxo-4-amino-1, 2-dihydropyrimidin-1-yl)-2-deoxy-2, 2-difluororibose; 2`, 2`-DFDC; 2`, 2`-difluoro-2`-deoxycytidine; 2`, 2`-difluorodeoxycytidine; 2`-deoxy-2`-difluorocytidine; 2`Deoxy-2`, 2`-Difluorocytidine; 2, 2 difluorodexoycytidine; 2H-1, 3, 2-Oxazaphosphorin-2-amine, N, N-bis(2-chloroethyl)tetrahydro-, 2-oxide; 2H-1, 3, 2-oxazaphosphorin-2-amine, N, N-is(2-chloroethyl)tetrahydro-, 2-oxide; Active Follow-up; Adjuvant; Allogenic; Allogenic Cell Vaccine; allogenic tumor cell vaccine; Antibodies; Antigens; Antineoplastic Vaccine; Arm; ATGN; Avidity; base; biological signal transduction; cancer cell; Cancer Vaccines; Cancers; Carloxan; CD152; CD152 Antigen; CD4 lymphocyte; CD4 Positive T Lymphocytes; CD4 T cells; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CD8; CD8B; CD8B1; CD8B1 gene; Cell Communication and Signaling; Cell Signaling; Cells, CD4; chemotherapy; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; Clinical; Clinical Trials, Phase I; Clinical Trials, Phase II; cohort; Combined Vaccines; CTLA 4; CTLA-4 antigen; CTLA4; CTLA4 Protein; CTLA4-TM; CTX; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamide; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; cytotoxic T-lymphocyte antigen 4; Cytotoxic T-Lymphocyte Protein 4; Cytotoxic T-Lymphocyte-Associated Antigen 4; Cytotoxic T-Lymphocyte-Associated Protein 4; Cytotoxic T-Lymphocyte-Associated Serine Esterase-4; Cytoxan; Data; Development; dFdC; dFdCyd; Difluorodeoxycytidine; Disease; Disease Resistance; disease/disorder; Disorder; Dose; Early-Stage Clinical Trials; Endoxan; Endoxana; Enduxan; enroll; Enrollment; Evaluable; Evaluable Disease; experience; follow-up; Fosfaseron; Gastrointestinal Tract, Pancreas; gemcitabine; Gene-Modified; Genes; Genoxal; Genuxal; GM-CSF; GMCSF; granulocyte macrophage colony stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor; helper T cell; Histamine-Producing Cell-Stimulating Factor; HOSP; Hospitals; host response; Immune; Immune response; immune system tolerance; immune therapy; Immune Tolerance; immune unresponsiveness; immunogen; Immunologic Tolerance; Immunologic, Immunochemical; immunological paralysis; Immunologically Directed Therapy; Immunologics; immunoresponse; Immunotherapy; in vivo; innovate; innovation; innovative; Intracellular Communication and Signaling; ITX; Ledoxina; LYT3; malignancy; Malignant Cell; Malignant neoplasm of pancreas; Malignant Neoplasms; Malignant Pancreatic Neoplasm; Malignant Tumor; megakaryocyte potentiating factor; mesothelin; Metastatic Pancreatic Adenocarcinoma; Mitoxan; Molgramostin; neoplasm/cancer; neoplastic cell; Neosar; Pancreas; Pancreas Cancer; Pancreas Neoplasms; Pancreatic; Pancreatic Cancer; pancreatic neoplasm; Pancreatic Tumor; Patients; Phase 1 Clinical Trials; phase 1 study; phase 1 trial; Phase 2 Clinical Trials; phase 2 study; phase 2 trial; Phase I Clinical Trials; Phase I Study; phase I trial; Phase II Clinical Trials; phase II trial; Procytox; Progression-Free Survivals; protocol, phase I; protocol, phase II; public health relevance; randomisation; randomization; Randomized; randomly assigned; recruit; Recruitment Activity; Resistance; resistance to disease; Resistance, Disease; resistant; resistant disease; resistant to disease; response; Safety; Sendoxan; Signal Transduction; Signal Transduction Systems; Signaling; Soluble Mpf/Mesothelin-Related Protein; Staging; study, phase II; Syklofosfamid; T-Cells; T-Lymphocyte; T4 Cells; T4 Lymphocytes; TC-GM-CSF; Testing; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; Toxic effect; Toxicities; tumor; Tumor Antigens; Tumor Cell; Tumor of the Pancreas; Tumor-Associated Antigen; Tumor-Cell Human GM Colony-Stimulating Factor; tumor-specific antigen; Upper arm; Vaccines; Vaccines, Combination; Vaccines, Combined; Vaccines, Neoplasm; Vaccines, Tumor; Zytoxan
Project start date: 2008-07-03
Project end date: 2011-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2011
PFA/PA: PAR-06-451
5R21CA126058-02 (2009): $330569
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Daniel A Laheru
Gene Modified Vaccine In Combination With Ipilimumab For Advanced Pancreatic Canc
Daniel A Laheru
Oncology, Sidney Kimmel Comprehensive Cancer Centejohns Hopkins University
w400 Wyman Park Building
baltimore, Md 21218
Grant 1R21CA126058-01A2 from National Cancer Institute IRG: CONC
Abstract: The broad objective of this proposal is to test the hypothesis that there is an association of immunologic responses with clinical responses in patients with metastatic pancreatic adenocarcinoma treated with anti-CTLA-4 (Ipilimumab) alone and in combination with vaccine. This study will assess safety, efficacy, and immune activation in these patients. An irradiated GM-CSF-gene modified allogeneic pancreatic cancer vaccine would provide shared immunodominant tumor antigens that could subsequently recruit and activate tumor specific T cells. The use of this vaccine has been shown to be safe and feasible in the adjuvant setting integrated with chemoradiation. In addition, it has been shown to induce mesothelin-specific T cells in the adjuvant setting and when combined with immune modulating doses of cyclophosphamide in the metastatic setting. One of the obstacles to an effective immune therapy is the induction of immune tolerance to cancer cells. One of the agents under development to modulate immune tolerance is an antibody to cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), which is transiently upregulated on activated T cells and provides an inhibitory signal to T cells undergoing activation. It is also constitutively activated on regulatory T cells (Tregs). This proposal aims to evaluate Ipilimumab in patients with metastatic pancreatic cancer. In addition, we will build on our experience with the gene-modified pancreatic cancer vaccine by combining GM-CSF based vaccines with an antibody to CTLA-4. Patients will be enrolled in groups of 3. We will escalate the treatment through 4 stages Ipilimumab 5mg/kg alone, Ipilimumab 5mg/kg + vaccine, Ipilimumab 10mg/kg alone, and Ipilimumab 10mg/kg + vaccine. Since previous studies have shown an association between toxicity and response, we will consider a toxicity level of <33% to be acceptable. The cohorts of the maximum dose Ipilimumab alone and Ipilimumab + vaccine for which the toxicity is <33% will be expanded in order to refine the estimates of toxicity and efficacy. A 21 randomization schema favoring the combination group will be used to allocate patients up to a total of 33 evaluable patients. The primary objective is to characterize the safety profile and immune responses in patients treated with Ipilimumab alone and Ipilimumab in combination with vaccine. The secondary objectives are to estimate response rate, progression-free survival, and overall survival in each of the study arms separately. This proposal aims to combine Ipilimumab with a pancreatic cancer vaccine in patients with metastatic disease. Ipilimumab is an agent that may enhance the body´s immune response to the vaccine and ultimately to the cancer
Project start date: 2008-07-03
Project end date: 2010-06-30
1R21CA126058-01A2 (2008): $330569
Gene Modified Cell Lines As Vaccine For Pancreas Cancer
Daniel A Laheru
Johns Hopkins University W400 Wyman Park Building Baltimore, Md 212182680
Grant 5K23CA093566-05 from National Cancer Institute IRG: NCI
Abstract: Pancreatic cancer is the fourth leading cause of cancer related deaths in the US. Although surgical resection is the only curative option, the median survival is only 15-19 months for resectable stage 1,2 and 3 disease. For patients who present with metastatic disease, the median survival is 3-6 months. The addition of chemotherapy and/or radiation therapy in select settings have resulted in only modest clinical benefits. Therefore, more effective therapies are urgently needed. The central theme of this grant proposal is to optimize immunotherapy for pancreatic cancer by designing and conducting clinical trials using genetically modified pancreatic tumor cell lines as vaccine that would improve on the outcome of (1) patients with pancreatic adenocarcinoma following surgical resection when given in combination with chemoradiation (Specific Aim #1); and (2) patients with primary metastatic or relapsed disease when given in sequence with immune modulating doses of Paclitaxel or with cytoreductive doses of Gemcitabine (Specific Aim #2). We hypothesize that (1) Biologic endpoints that include the measurement of post vaccination delayed type hypersensitivity (DTH) responses to autologous tumor (adjuvant study) or to mutated k-ras peptides (metastatic study) and the measurement of the immune infiltration at the vaccine site can correlate with clinical endpoints such as overall and disease-free survival. (2) Measurement of serum GM-CSF levels as a measure of longevity of the vaccine cells following each vaccination can provide an improved understanding of the in vivo kinetics of the allogeneic cells at the vaccine site and will allow for the optimization of the vaccine boosting schedule. (3) The vaccine is associated with minimal toxicities and can be safely integrated with chemotherapy and radiation therapy. The design of Specific Aim #1 is a single institution Phase II study of vaccine in combination with adjuvant chemoradiotherapy for the treatment of pancreatic adenocarcinoma following surgical resection. The study will enroll 60 patients over 2 years. The design of Specific Aim #2 is a single institution randomized study of vaccine in sequence with Gemcitabine or with Paclitaxel in patients with primary metastatic or relapsed pancreatic adenocarcinoma. This study will enroll 120 patients over 2 years. If these studies demonstrate anti-tumor immunity that is associated with prolongation of disease free survival, they will lead to the design and conduction of multi-center phase III studies. Ultimately, these studies could lead to the approval of a new therapeutic option for pancreatic cancer, which is currently fatal in most patients. In addition, data from these studies could contribute to a better understanding of how to schedule multiple vaccine boosts. Finally, these data will provide valuable information on how to best integrate the vaccine with other therapeutic modalities including surgery, radiotherapy and chemotherapy.
Keywords: active immunization, drug design /synthesis /production, human therapy evaluation, neoplasm /cancer immunotherapy, neoplasm /cancer vaccine, pancreas neoplasm, vaccine development, colony stimulating factor, combination cancer therapy, delayed hypersensitivity, gemcitabine, longitudinal human study, metastasis, neoplasm /cancer chemotherapy, neoplasm /cancer radiation therapy, neoplasm /cancer relapse /recurrence, neoplasm /cancer surgery, outcomes research, paclitaxel, biopsy, cell line, clinical research, human subject, neoplastic cell, patient oriented research
Project start date: 2002-09-14
Project end date: 2007-07-31
5K23CA093566-05 (2006): $136890
5K23CA093566-04 (2005): $136890
5K23CA093566-03 (2004): $136890
5K23CA093566-02 (2003): $136890
1K23CA093566-01A1 (2002): $136890