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DR. JABLONS: We have been very involved in development of GVAX®, a vaccine-based approach that utilizes autologous tissue. The methodology, developed by Cell Genesys, initially was developed based on preclinical work performed by Glenn Dranoff, MD, at the Dana-Farber Cancer Institute in Boston.
The rationale for GVAX was to understand how, in some patients, tumors developed without detection by the immune system. Could it be due to tumor-host immunosuppression, imbalances, or regulatory cells, for example? Would there be some way to override those factors? Dranoff and colleagues investigated approximately 20 different cytokines in vivo and in vitro thought to be capable of “reawakening” the immune response, especially to stimulate the key regulators of antigen presentation, in particular the dendritic cell populations. GM-CSF stood out as the most potent of the various cytokines tested.
The GVAX experience has taught us that immuno-based therapy for lung cancer, even advanced-stage disease, is possible.
This approach utilizes autologous tumor tissue in the absence of having the “Holy Grail” of tumor immunotherapy: defined tumor antigen. It involves removing the tumor and sending it to a single central processing site for an ex vivo transduction with adenoviral-based vector that carries the cassette (in this case, the GM-CSF gene) to make the protein that is critical for stimulation of the immune response. The transduced cells are then irradiated so they will not continue to produce cancer when reinjected into the patient.
Development of GVAX is more complicated in lung cancer, which is a heterogeneous disease. The approach for lung cancer would be to obtain the whole tumor and attempt to identify the cancer-specific antigen. Then the application of an immune stimulant would be utilized to promote the endogenous immune response.
Several small phase II trials of GVAX in NSCLC have shown the potential and feasibility of this approach more so than any real efficacy. Unfortunately, GVAX has been abandoned by the company—not for lack of potential, but because of the difficulty of working with autologous tumor tissue. Nevertheless, in cancers such as NSCLC, patients with early-stage disease typically undergo surgical resection, and the tumor tissue obtained would be an ideal source of antigens for an autologous vaccine.
The first phase I/II trial of GVAX in NSCLC included 1 cohort: completely resected stage I and II patients. The difficulty of the study was that this population had to be followed for a long period of time. The data failed to show an obvious advantage for GVAX.
Subsequent phase II trials focused on patients with stage IIIB/IV NSCLC. A challenge associated with this approach in patients with advanced-stage NSCLC was how to get the tumor to transduce outside of the body. A protocol amendment limited tumor harvest to minor surgical procedures, and the predominant sources of tumor became pleural effusions, accessible lymph nodes, and soft tissue. However, pleural effusions and lymph node biopsy materials may also be a source of immune-regulatory cytokines.
In the second phase II trial in advanced-stage NSCLC, 3 of 26 (12%) patients had complete pathologic responses to GVAX, which tended to be durable. Survival was in the range of 26 to 30 months. Delayed-type hypersensitivity (DTH) responses tended to correlate with survival, suggesting that lung cancer is an immunogenic tumor susceptible to immune modulation.
Patients with lung cancer who responded to GVAX tended to have the bronchoalveolar carcinoma (BAC) subtype. Stage IV patients with that subtype typically do quite well long-term. It remains unclear whether the durable response to GVAX in this patient population was reliable; nonetheless, it was an exciting signal.
In the next-generation trial in lung cancer patients, autologous tumor tissue was mixed with irradiated K652 erythroleukemia cells, which produce high levels of GM-CSF: No patients responded to therapy. In a final trial, some patients with BAC (which may have a viral etiology) responded to GVAX. We and others are now investigating that association.
A phase II trial of GVAX in patients with surgically resected stage IIIb/IV NSCLC was conducted by the Southwestern Oncology Intergroup. Among 88 treated patients, there was no dramatic efficacy signal.
The GVAX experience has taught us that immuno-based therapy for lung cancer, even advanced-stage disease, is possible. The success rate for vaccine production was remarkably high. Even though the methodology by which the GVAX vaccine was produced for each patient was cumbersome, the production process did work.
Although Cell Genesys is not pursuing further development of GVAX vaccine in lung cancer at this time for a number of reasons, the vaccine provided an interesting treatment option for patients. Many of the lung cancer patients we see in our practices have failed first-, second-, or third-line therapies and may have relatively good performance status, but may be hampered by malignant pleural effusions. The GVAX vaccine afforded a treatment option for that population.
The more we understand about the cytokine balance—both for stimulating immune responses and avoiding regulatory responses—the more promising the future of this immunomodulatory approach.
Chief, Section of General Thoracic Surgery
Professor of Surgery
University of California, San Francisco
San Francisco, California
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Pedro Romero, MD
Håkan Mellstedt, MD, PhD
David Carbone, MD, PhD
David Jablons, MD
Charles A. Butts, MD
Philip Bonomi, MD
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Autologous Tumor Cell Vaccines for NSCLC: The GVAX ExperienceDavid Jablons, MD |
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