Dr. James Gulley Clinical Trials
Research Profile of Dr. Gulley.
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Novel Immunotherapeutic Approaches Employing Cancer Vaccines
The specific aims of the Clinical Trials Group are to conduct clinical trials (a) to evaluate the combined use of vaccines and local radiation of tumors, (b) to evaluate the effects of intratumoral vaccination alone and in combination with systemic vaccinations, and (c) to evaluate the role of vaccines with other immunostimulatory agents to control and/or eliminate established tumors. Dr. Gulley has focused on these novel immunotherapies and therapeutic approaches in patients with gastrointestinal and genitourinary tumors.
As Director of the Clinical Trials Group of the LTIB, Dr. Gulley plans and conducts clinical trials involving the use of cancer vaccines and other immunostimulatory molecules to modulate the immune response in cancer patients and to enhance vaccine-mediated killing. He works closely with the research scientists within the LTIB in the development of hypothesis-driven preclinical studies leading to the design of the science-driven clinical studies that he directs.
Since local radiation of tumor is a standard of care for both definitive and palliative treatment of many cancer types, the addition of vaccines to tumor radiation, with minimal likelihood of added toxicity and potential clinical synergy, presents a novel focus of study. Dr. Gulley has made important contributions to this area of clinical research. Scientists within the LTIB have shown that radiation of tumor cells can induce phenotypic alterations that facilitates T-cell mediated killing. This has been shown in both murine models and employing human cells in vitro. Dr. Gulley’s initial trial enrolled 48 patients with clinically localized prostate cancer and added vaccine to definitive local radiation. Dr. Gulley demonstrated that not only can immune responses be generated in the face of local radiation of tumor in the majority of patients and that this combination is safe, but also that there is evidence of immune-mediated tumor killing seen by de novo formation of T-cell responses to antigens found in prostatic cancers but not found in the vaccine. This phenomenon of antigen cascade is being carefully studies by other scientists of the LTIB and represents an important resonance between bench and bedside in elucidating immunologic and anti-tumor phenomena. A second clinical trial combining vaccine and radiation therapy is actively enrolling patients with CEA-positive tumors and liver metastasis. This is a paradigm-shifting trial since radiation of tumor is not a standard of care for liver metastases, but is being employed in this trial to modulate the phenotype of tumor cells as to render them more susceptible to T-cell-mediated killing. Analysis of tumor biopsies on this study will seek to further expand in vitro data. A third study combining vaccine with a bone-seeking radionuclide for patients with prostate cancer metastatic to bone is currently in review.
Dr. Gulley has also worked closely with scientists at the LTIB involved in preclinical studies of intratumoral vaccination with TRICOM-based vaccines (containing three human T-cell costimulatory molecules, B7.1, ICAM-1 and LFA-3), and the combined use of intratumoral and systemic vaccinations. Consequently, Dr. Gulley opened the first trial utilizing intratumoral vaccination using recombinant vectors containing tumor associated antigen (TAA) and costimulatory molecules in patients with prostate cancer. This approach allows the tumor cells to act as antigen presenting cells having both signal 1 (TAA) and signal 2 (costimulatory molecules), and also makes them better targets for immune-mediated killing.
Dr. Gulley has also initiated an IND trial of a novel recombinant vaccine incorporating five different transgenes. Both the recombinant vaccinia used for the prime and the recombinant fowlpox used for the boost contain two TAA transgenes (CEA and MUC-1), as well as transgenes for three human T-cell costimulatory molecules (B7.1, ICAM-1 and LFA-3). The transgenes for CEA and MUC-1 also contain the agonist epitopes identified in LTIB. This vaccine has demonstrated immunologic responses and early evidence of clinical response with one ovarian cancer patient having a dramatic sustained clinical response.
Another trial recently initiated by Dr. Gulley in patients with prostate cancer utilizes a PSA-TRICOM-based vaccine regimen with anti-CTLA-4. Preclinical studies in the LTIB have shown that the use of TRICOM-based pox vectors with anti-CTLA-4 MAb enhances the level of T-cell responses, the avidity of T cells generated, and enhances anti-tumor responses. By preventing interactions between CTLA-4 and its ligands via a blocking antibody, it is possible to sustain and potentiate immune responses against weak antigens. This phase I trial recently opened and is the first to use anti-CTLA-4 with viral vector vaccines and with the use of positive T-cell costimulation.
Dr. Gulley completed the first clinical trials with rV-, rF-PSA-TRICOM vaccines in patients with metastatic prostate cancer, providing evidence of clinical activity that correlated with the generation of PSA-specific T-cell responses. These trials have led to planned NCI-sponsored randomized multicenter Phase II/III trials.
Dr. Gulley is also instrumental in the programmatic effort in the design and development of clinical trials, and the review and execution of vaccine protocols for a range of institutions throughout the United States. These include clinical trials ongoing or in the review or planning stages at Duke, Cornell, Columbia, Cancer Institute of New Jersey, Tulane, OSU, Fox Chase Cancer Center, Georgetown, Dana Farber, Ohio State, U. Penn, Einstein and U. Nebraska, as well as ECOG. In addition, he is involved in data compilation, review and interpretation for many of these studies. As one example, Dr. Gulley designed and co-wrote a multi-institutional CTEP sponsored phase II trial that will be the first to combine vaccine, radiation therapy and chemotherapy for patients with unresectable pancreatic cancer.