Abstract PL03-02: Current status of recombinant pox-viral vaccines
Authors: Gulley James L. , Madan Ravi A. , Schlom Jeffrey 
Published: August 2012

Abstract
Therapeutic vaccines have now reached a tipping point in terms of agents and strategies leading to improved clinical outcomes, with great potential for the use of vaccines in combination with chemotherapy, radiation, hormonal therapy, and/or small molecule-targeted therapeutic agents. The first FDA-approved therapeutic cancer vaccine, sipuleucel-T, had 2 consistent phase III clinical trials showing a median improvement in survival of over 4 months, with limited toxicity, in patients with metastatic prostate cancer.1,2 In what now appears to be a class effect for the use of therapeutic vaccines as monotherapy alone, neither trial showed an improvement in progression-free survival (PFS). These definitive proof-of-principle trials have increased our understanding of the potential for clinical benefit from therapeutic vaccines and the design of clinical trials. However, sipuleucel-T has the increased cost and logistical implications of an autologous product.
PROSTVAC
This off-the-shelf therapeutic cancer vaccine developed at NCI is composed of poxviral vectors (vaccinia prime with fowlpox boost) containing PSA and 3 human T-cell costimulatory molecules (PSA-TRICOM, designated PROSTVACTM). The NCI is continuing clinical development of this vaccine via a CRADA with Bavarian Nordic Immunotherapeutics, Mountain View, CA. Preclinical studies showed the importance of providing additional T-cell costimulation to poxviral vectors for optimal antitumor effect, leading to the development of poxviral vectors containing full-length genes for tumor-associated antigens and a triad of costimulatory molecules (ICAM-1, LFA-3, and B7.1) known as TRICOM. Early clinical trials with poxviral vectors established the safety and immunogenicity of these agents.5,6
We have recently published a multicenter phase II trial employing the third generation of PSA-TRICOM in patients (n = 125) with metastatic prostate cancer.7 The 43-center, randomized, placebo (empty vector)-controlled, company-sponsored trial, much like the sipuleucel-T trials, showed no evidence of improved PFS (the primary endpoint), but a statistically significant improvement in median overall survival (OS) (25.1 vs. 16.6 months; p = 0.006), with a 44% reduction in death rate. The vaccine was well tolerated.
We also recently completed a concurrent phase II study of PSA-TRICOM at the NCI that demonstrated an increase in PSA-specific T cells by IFN-γ ELISPOT in about 50% of patients, with a trend to improved outcomes in patients with the best immune response.8 This study demonstrated a similar median OS (26.6 months). Hypothesis-generating data from this study suggest that a substantially greater observed survival benefit came from the subgroup of patients with longer predicted survival (associated with lower tumor burdens), based on a validated nomogram, than for patients with shorter predicted survival. Subsequent analysis of data also demonstrated that unlike treatment with chemotherapy, patients treated with PROSTVAC vaccine demonstrated declines in tumor growth rate post-vaccination.9
A phase III trial of PSA-TRICOM in patients with metastatic prostate cancer was initiated in 2011. This global trial is enrolling men (n = 1,200) with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer and randomizing them to PSA-TRICOM with GM-CSF given at the injection site, PSA-TRICOM with placebo GM-CSF, or wild-type fowlpox with placebo GM-CSF. The primary endpoint of this study is OS.
PANVAC
Another off-the-shelf vaccine developed at the NCI is PANVAC. This poxviral vector platform utilizes vaccinia and fowlpox expressing CEA and MUC-1 along with TRICOM. Initial studies showed safety and immunogenicity, with early evidence of clinical benefit in some patients.10,11 A multicenter trial initiated at Duke University in patients with metastatic colorectal cancer (n = 72) was recently presented. Patients enrolled on this study had no radiographic evidence of disease after surgical resection of hepatic or pulmonary metastases. These patients are at very high risk for recurrence and death from cancer. Patients were randomized to receive vaccine s.c. or an infusion of dendritic cells incubated with the vector. Differences in PFS and OS between the arms were minimal; however, when compared with a concurrent control group of patients with similar baseline characteristics, while PFS was similar, OS curves were strikingly different, with a 75% 2-year OS in the control (similar to other reported studies in this patient population) vs. 97% in the combined vaccine-treated patients. A phase III OS trial to follow up on these results is being planned.
Combination studies
Unlike sipuleucel-T, which is given 3 times over a treatment period of one month, the poxviral-vector vaccines mentioned above are typically given monthly until disease progression or until a new therapy is required, expanding the potential for combination with other agents. In preclinical studies, we have shown that cytotoxic therapies (e.g., chemotherapy or radiation therapy) can alter the phenotype of tumor cells, facilitating immune recognition and/or tumor cell killing. We have completed studies wherein vaccine combined with chemotherapy, radiation therapy, and hormonal therapy was still able to generate immune responses. Clinical endpoint studies combining poxviral vaccine with these standard-of-care modalities vs. standard-of-care alone are ongoing. We have also recently completed a safety study of PROSTVAC combined with ipilimumab, which blocks negative costimulation. Up to 10 mg/kg of ipilimumab was safely administered with a vaccine that enhances positive costimulation. Immune-related adverse events were similar in proportion and grade to those previously reported with ipilimumab alone. Furthermore, while the median predicted survival was about 18 months based on a validated nomogram, actual median OS exceeded 34 months in this phase I study.
References
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9 Stein WD, Gulley JL, Schlom J, et al. Tumor regression and growth rates determined in five intramural NCI prostate cancer trials: the growth rate constant as an indicator of therapeutic efficacy. Clin Cancer Res 2011; 17: 907-17.
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Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr PL03-02. doi:1538-7445.AM2012-PL03-02