A phase II study of PROSTVAC-VF vaccine, and the role o f GM-CSF, in patients (pts) with metastatic androgen insensitive prostate cancer (AIPC)

274

160

Purpose: Docetaxel has activity against androgen-independent prostate cancer and preclinical studies have shown that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine if concurrent docetaxel (with dexamethasone) had any effect on generating animmune responseto the vaccine. Secondary endpoints were whether vaccine could be given safely with docetaxel and the clinical outcome of the treatment regimen. Experimental Design: The vaccination regimen was composed of (a) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (b) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (c) sequential booster vaccinations with recombinant fowlpox virus (rF-) containing the PSA gene (rF-PSA). Patients received granulocyte macrophage colony-stimulating factor with each vaccination. Twenty-eight patients with metastatic androgen-independent prostate cancer were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. The ELISPOT assay was used to monitor immune responses for PSA-specificTcells. Results: The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancerâ ssociated tumor antigens were also detected postvaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median progressionfree survival on docetaxel was 6.1months after receiving vaccine compared with 3.7 months with the same regimen in a historical control. Conclusion: This is the first clinical trial to show that docetaxel can be administered safely with immunotherapy without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings.Adenocarcinoma of the prostate is the most common noncutaneous malignancy diagnosed in American males and the second leading cause of cancer death. One of six men will develop clinically significant prostate cancer in his lifetime.During 2005, an estimated 232,900 men will be diagnosed with prostate cancer and 30,350 will die from the disease in the United States (1). Overall survival for patients with metastatic androgen-independent prostate cancer has been improved with a docetaxel-based regimen. The clinical benefit shown in these recent studies is an f3-month increase in survival using an every-3-week regimen of docetaxel (2, 3). However, compared with the every-3-week schedule, weekly docetaxel is associated with significantly less grade 3 or 4 hematologic toxicity. Other studies have looked at combining weekly docetaxel with other agents (4, 5). A random...

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer.

Arlen

Gulley

Parker

et al. 2006

274

160

“…27). Recent phase I/II trials in patients with metastatic and locally advanced prostate cancer have shown clinical responses and drops in serum PSA (28). A company-sponsored multicenter randomized phase II study in 125 patients with metastatic androgen-independent asymptomatic prostate cancer did not meet its primary end point of progression-free survival (29).…”

Section: Vaccine Clinical Trialsmentioning

confidence: 99%

Cancer Vaccines: Moving Beyond Current Paradigms

Schlom

Arlen

Gulley

2007

189

141

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.The field of cancer vaccines is currently in a state of active preclinical and clinical investigations. Although no therapeutic cancer vaccine has been approved to date by the Food and Drug Administration, recent preclinical and clinical findings have shown that appropriate clinical trial design and end points, and the use of vaccines in new paradigms of combination therapies may well lead to cancer vaccines ultimately being used for the therapy of several cancer types.Cancer vaccines differ from other therapies in that they initiate a dynamic process of activating the host's own immune system. This process could potentially influence both how patient responses are evaluated and how responses to subsequent therapies post-vaccination are evaluated. Evaluation of Cancer Vaccines: New Paradigms for Responses toTherapyIt is proposed that cancer vaccines are a therapeutic modality where one should evaluate ''patient response'' more so than ''tumor response.'' The two phenomena are not always mutually inclusive. Standardization of response criteria is of course critical for any given clinical trial, but one must be aware that the use of only one criterion for all therapeutics, cancer types, and disease stages can be classic ''paradigm paralysis.'' Response Evaluation Criteria in Solid Tumors (RECIST; refs. 1, 2) has served the oncology community well in the evaluation of passive therapeutic modalities, such as chemotherapeutic agents and radiation therapy. With the advent of new targeted therapies, including cancer vaccines, however, the sole use of RECIST criteria as a clinical e...

“…Previous studies have shown that poxviral vaccine strategies can be used safely in patients with advanced cancer, can overcome immunologic tolerance, and have been associated with clinical benefit in some patients (7,8,11). Here we report a pilot study of 25 patients treated with a poxviral vaccine consisting of genes for the TAAs CEA and MUC-1, along with TRICOM (designated PANVAC).…”

mentioning

confidence: 99%

“…Two vectors, vaccinia and fowlpox, have been engineered to express both CEA and MUC-1, with a single amino acid substitution in each gene designed to make the gene product more immunogenic (5,6). The use of agonist epitopes within the TAA has been associated with clinical responses (7,10,11). Vectors directed against multiple TAAs may evoke additive or synergistic immune responses and could play an important role in overcoming antigenic escape variance.…”

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confidence: 99%

Pilot Study of Vaccination with Recombinant CEA-MUC-1-TRICOM Poxviral-Based Vaccines in Patients with Metastatic Carcinoma

Gulley¹,

Arlen²,

Tsang³

et al. 2008

200

139

Purpose: Poxviral vectors have a proven safety record and can be used to incorporate multiple transgenes. Prior clinical trials with poxviral vaccines have shown that immunologic tolerance to self-antigens can be broken. Carcinoembryonic antigen (CEA) and MUC-1are overexpressed in a substantial proportion of common solid carcinomas. The primary end point of this study was vaccine safety, with immunologic and clinical responses as secondary end points. Experimental Design:We report here a pilot study of 25 patients treated with a poxviral vaccine regimen consisting of the genes for CEA and MUC-1, along with a triad of costimulatory molecules (TRICOM; composed of B7.1, intercellular adhesion molecule 1, and lymphocyte function^associated antigen 3) engineered into vaccinia (PANVAC-V) as a prime vaccination and into fowlpox (PANVAC-F) as a booster vaccination. Results: The vaccine was well tolerated. Apart from injection-site reaction, no grade z2 toxicity was seen in more than 2% of the cycles. Immune responses to MUC-1 and/or CEA were seen following vaccination in 9 of 16 patients tested. A patient with clear cell ovarian cancer and symptomatic ascites had a durable (18-month) clinical response radiographically and biochemically, and one breast cancer patient had a confirmed decrease of >20% in the size of large liver metastasis. Conclusions: This vaccine strategy seems to be safe, is associated with both CD8 and CD4 immune responses, and has shown evidence of clinical activity. Further trials with this agent, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted.