Purpose: This trial evaluated the safety, clinical activity, and immunogenicity of an allogeneic cellular immunotherapy in 55 chemotherapy-naive patients with hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, is a combination of two prostate carcinoma cell lines modified with the granulocyte macrophage colony-stimulating factor (GM-CSF) gene. Experimental Design: HRPC patients with radiologic metastases ( n = 34) or rising prostate-specific antigen (PSA) only ( n = 21) received a prime dose of 500 million cells and 12 boost doses of either 100 million cells (low dose) or 300 million cells (high dose) biweekly for 6 months. End points were changes in PSA, time to progression, and survival. Results: Median survival was 26.2 months (95% confidence interval, 17, 36) in the radiologic group: 34.9 months (8, 57) after treatment with the high dose ( n = 10) of immunotherapy and 24.0 months (11, 35) with the low dose ( n = 24). The median time to bone scan progression in the radiologic group was 5.0 months (2.6, 11.6) with the high dose and 2.8 months (2.8, 5.7) with the low dose. In the rising-PSA group ( n = 21) receiving the low dose, the median time to bone scan progression was 5.9 months (5.6, not reached), and median survival was 37.5 months (29, 56). No dose-limiting or autoimmune toxicities were seen; the most common adverse events were injection site reaction and fatigue. Conclusions: These results suggest that this GM-CSF–secreting, allogeneic cellular immunotherapy is well tolerated and may have clinical activity in patients with metastatic HRPC. Phase 3 trials to confirm these results are under way.

https://clincancerres.aacrjournals.org/content/clincanres/13/13/3883.full.pdf

Granulocyte macrophage colony-stimulating factor--secreting allogeneic cellular immunotherapy for hormone-refractory prostate cancer.

The field of cancer vaccines is currently in an active state of preclinical and clinical investigations. Although no therapeutic cancer vaccine has to date been approved by the Food and Drug Administration, several new paradigms are emerging from recent clinical findings both in the use of combination therapy approaches and, perhaps more importantly, in clinical trial design and end point analyses. This article will review recent clinical trials involving several different cancer vaccines from which data are emerging contrasting classic “tumor response” (Response Evaluation Criteria in Solid Tumors) criteria with “patient response” in the manifestation of increased patient survival post-vaccine therapy. Also described are several strategies in which cancer vaccines can be exploited in combination with other agents and therapeutic modalities that are quite unique when compared with “conventional” combination therapies. This is most likely due to the phenomena that ( a ) cancer vaccines initiate a dynamic immune process that can be exploited in subsequent therapies and ( b ) both radiation and certain chemotherapeutic agents have been shown to alter the phenotype of tumor cells as to render them more susceptible to T-cell–mediated killing. Consequently, evidence is emerging from several studies in which patient cohorts who first receive a cancer vaccine (as contrasted with control cohorts) benefit clinically from subsequent therapies.

/pdf/cancer-vaccines-moving-beyond-current-paradigms-2nh1rz5wgs.pdf

Cancer Vaccines: Moving Beyond Current Paradigms

GVAX is a granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transfected tumor cell vaccine. Original work with GM-CSF as a recombinant DNA protein (Leukine) involved proliferative stimulation of macrophages and neutrophils for the purpose of reducing hematopoietic toxicity related to dose-intensive chemotherapy. Following US Food and Drug Administration approval of Leukine several years ago, extensive preclinical results have demonstrated an immunostimulatory effect related to GM-CSF gene when transfected into tumor cells and used as a vaccine (GVAX). Tumor regression and prolonged survival was demonstrated in animal models. Toxicology with GVAX indicated no adverse effects, which enabled further testing in cancer patients. A small number of responses were demonstrated in Phase I trials in immunosensitive cancer patients (renal cell carcinoma and melanoma). However, a series of dramatic complete and durable responses in advanced non-small cell lung cancer patients, demonstrated in recent clinical trials, have generated interest in further development of this vaccine in nontraditional cancer disease types. The rationale of GVAX development and a summary of clinical results are reviewed.

Vaccines in cancer: GVAX®, a GM-CSF gene vaccine

GVAX cancer immunotherapies are composed of whole tumor cells genetically modified to secrete the immune stimulatory cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), and then irradiated to prevent further cell division. Both autologous (patient specific) and allogeneic (non-patient specific) GVAX platforms have been evaluated either as single agents or in combination with other immunomodulatory strategies. Many early-phase clinical trials have now been completed. Results have consistently demonstrated a favorable safety profile manifested primarily by injection site reactions and flu-like symptoms. Consistent evidence of immune activation and clinical activity, including radiologic tumor regressions, has been seen across multiple cancer indications in both early- and late-stage disease. Phase 3 trials evaluating an allogeneic GVAX immunotherapy product in prostate cancer are under way.

GM-CSF gene-modifed cancer cell immunotherapies: of mice and men.

Prostate Cancer Gene Therapy Clinical Trials

4565 Background A prior phase 2 study of allogeneic prostate carcinoma cell lines (PC-3 and LNCaP) genetically modified to secrete GM-CSF in 34 metastatic HRPC patients (pts) yielded a median survi...

A phase 2 study of an allogeneic GM-CSF gene-transduced prostate cancer cell line vaccine in patients with metastatic hormone-refractory prostate cancer (HRPC)

2517 BackgroundA phase 2 study of allogeneic prostate carcinoma cell lines (PC-3 and LNCaP) genetically modified to secrete GM-CSF (GVAX) in 34 met HRPC patients (pts) yielded a median survival of 26 months (Proc ASCO, Vol. 21:183a, 2002). To confirm clinical activity and safety prior to initiation of phase 3 trials a second, expanded Phase 2 study was performed. Methods 80 met HRPC pts were treated for 24 wks. Doses (in millions of cells) ranged from 100 monthly to 500 prime/300 boost bi-weekly. Pts were monitored by bone scans and PSA. Tumor reactive antibodies (ab) were measured by Western blot (WB) of vaccine lysates against pt sera. Bone destruction was monitored by ICTP, a marker of osteoclast activity. Results 80 pts enrolled and completed treatment, and have been followed thus far for a median of 15.0 months with no DLTs observed. Stable or improved bone scans were observed in 43% (31/72) of pts. Stable or decreasing ICTP levels occurred in 62% (34/55) of pts. The median survival has not yet been ...

Clinical and immunologic findings in a phase 2 study of a GM-CSF-secreting prostate cancer cell line vaccine in patients with metastatic hormone-refractory prostate cancer (met HPRC)

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A phase 2 study of an allogeneic GM-CSF gene-transduced prostate cancer cell line vaccine in patients with metastatic hormone-refractory prostate cancer (HRPC)

Clinical and immunologic findings in a phase 2 study of a GM-CSF-secreting prostate cancer cell line vaccine in patients with metastatic hormone-refractory prostate cancer (met HPRC)