BIO-BUZZ: QUADRAMET�: A New Option for Hormone-Refractory Prostate Cancer?

BIO-BUZZ

QUADRAMET^®: A New Option for Hormone-Refractory Prostate Cancer?

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cancer is the most common noncutaneous cancer in men and is the cause of approximately 30,000 deaths per year in the U.S.¹ Vaccines for prostate cancer, which have been demonstrated to generate immunologic responses, are beginning to show significant promise in various clinical trials. Currently, numerous therapeutic options are being investigated, including

autologous and allogeneic whole-tumor cell vaccines, dendritic cell vaccines, and poxvirus-based vaccines. Advances in our understanding of the immunology of cancer have translated into new, more complex therapeutic strategies.

The treatment of hormone-refractory prostate cancer often represents a therapeutic challenge. As the most common malignancy in men and the second-leading cause of cancer death in the US, the number of patients requiring posthormonal therapy is increasing. In the past, only patients with proven metastatic disease or those with local treatment failure received hormonal therapy. In addition, despite some initial success with hormonal therapy, the durability of response is often inadequate, and subsequent treatment is usually needed for these patients. With recent advances in our understanding of the immunogenesis of hormone-refractory prostate cancer, newer treatment targets are being identified.

Cytogen Corporation has announced that the National Cancer Institute (NCI) has initiated a randomized, phase II study to evaluate QUADRAMET® (samarium SM 153 lexidronam injection) in combination with a targeted therapeutic vaccine, prostate-specific antigen (PSA)-TRICOM, for patients with progressive, hormone-refractory prostate cancer who have failed docetaxel-based regimens.

The primary objective of the study is to determine whether there is improvement in 4-month progression-free survival for patients treated with the combination regimen, compared with those treated with QUADRAMET alone. The study is expected to enroll 68 patients. Currently, there is no standard of care for treating prostate cancer patients who have progressive disease following

docetaxel-based therapy.

QUADRAMET is a targeted radiopharmaceutical that consists of radioactive samarium and a tetraphosphonate chelator, ethylenediaminetetramethylenephosphonic acid (EDTMP). QUADRAMET is formulated as an isotonic solution of samarium-153 lexidronam for intravenous administration. It is currently approved for treating pain arising from cancer that has spread to the bone, and is administered as a single intravenous injection, usually on an outpatient basis.

PSA-TRICOM targets PSA. Two novel PSA-based vaccines have been developed: (1) a recombinant vaccinia virus containing the entire PSA transgene with a modified agonist epitope and three costimulatory molecule transgenes, rVPSA-TRICOM; and (2) a similar recombinant fowlpox virus, rF-PSATRICOM. In an earlier phase II trial, researchers demonstrated the clinical safety of a prime/boost vaccine strategy—priming with rV-PSA-TRICOM, with subsequent monthly boosts using rF-PSA-TRICOM.

Cytogen’s PSA-TRICOM is designed to introduce the genes for PSA and a proprietary TRIad of COstimulatory Molecules (B7-1, ICAM-1 and LFA-3) essential for maximizing the antitumor cellular immune response. This stimulates the activation and proliferation of an array of cytotoxic T-cells, which seek out and destroy cancer cells bearing any of the targeted epitopes.

NCI researchers previously presented the results of a preclinical study evaluating the ability of QUADRAMET to modulate phenotype and enhance killing of tumor cells.² Exposure to QUADRAMET resulted in upregulation of various surface molecules on cancer cells, including Fas (CD95), carcinoembryonic antigen (CEA), mucin 1 (MUC-1), intercellular adhesion molecule-1 (ICAM-1 or CD54), and major histocompatibility complex class I (MHC-1). Each of these molecules has been implicated in enhancing anti-tumor T-cell responses through diverse mechanisms. Down-regulation of these genes is a common mechanism used by tumors to escape immune recognition and elimination.

Subsequently, in an 8-week phase I study,³ 10 patients with androgen-independent prostate cancer with or without metastatic disease were treated with 2 x l08 pfu of rVPSA-TRICOM followed by 1 x 109 pfu of rFPSA-TRICOM, both with gene sequences for PSA and TRICOM. The mean age of patients enrolled in the study was 70 years (range, 63 to 79 years). The mean PSA at baseline was 434 ng/mL. Treatment was well tolerated. There were no grade 3 or 4 toxicities or deaths. The most common adverse events were injection site reactions and fatigue. Four patients had stable disease (with <25% increase in PSA) through week 8. Anti-PSA antibodies were not induced with therapy: however, anti-vaccinia titers increased in all patients.

This study demonstrated that vaccination with rV-PSA-TRICOM and rF-PSA-TRICOM is well-tolerated and generated an immune response to vaccinia. The investigators concluded that PSA-TRICOM represents a feasible therapeutic approach for further study in patients with prostate cancer.

Tumor cells can avoid immune system recognition and elimination by down-regulating, or masking or turning offsurface molecules involved in immune system attack. The up-regulation, or enhancement, of these surface molecules with QUADRAMET may increase the susceptibility of tumor cells to the immune system, and this could be synergistic with various immunotherapy approaches designed to treat cancers.

As Michael D. Becker, president and chief executive officer of Cytogen explained, “To date, single-agent, immune-based strategies for treating cancer have shown limited promise for treating well-established tumors or advanced disease. Published studies indicate that multimodality approaches incorporating immunotherapy, radiotherapy, and other approaches hold the greatest promise for clinical success. Based on existing clinical data demonstrating the safety and preliminary activity of PSA-TRICOM and the preclinical data revealing the synergy between QUADRAMET and immunotherapy, we believe this novel combination is a promising approach to cancer immunotherapy for prostate cancer patients.” The principal NCI investigator for the study is James L. Gulley, M., PhD, FACP, director of the Clinical Immunotherapy Group, Laboratory of Tumor Immunology and Biology. Additional information on the trial is available by contacting the coordinator at (301) 451-1228 or by visiting http://bethesdatrials. cancer.gov/clinical-research/search_detail. asp?ProtocolID=NCI-07-C-0106. Eligibility requirements are listed in the table.

The QUADRAMET/PSA-TRICOM trial has a solid foundation in terms of therapeutic rationale. The results of the previous preclinical and phase I studies warranted further investigation.

The results suggest that up-regulation of genes following exposure to QUADRAMET could make tumor cells more susceptible or amenable to attack by the immune system. These effects could be synergistic with various immunotherapy approaches that work by stimulating a patient’s immune system against cancer.

This research represents an important step forward in the use of QUADRAMET, which is currently used primarily as palliative therapy in patients with advanced, hormone-refractory disease. Based on emerging clinical data, QUADRAMET may prove to be a useful adjunct used to improve the response and duration of lesion control in combination with other therapeutic approaches. Moreover, the findings from these trials and the demonstrated potential to combine vaccines with conventional therapies suggest a promising future for the treatment of prostate cancer.

REFERENCES

1. National Cancer Institute. Prostate cancer. 2007. Available at: http://www.cancer.gov/cancertopics/types/ prostate. Accessed March 12, 2007.

2. Dipaola R, Plante M, Kaufman H, et al. A Phase I trial of Pox PSA vaccines (PROSTVAC®-VF) with B7-1, ICAM- 1, and LFA-3 co-stimulatory molecules (TRICOM™) in patients with prostate cancer. J Transl Med. 2006;4:1.

3. Gulley J, Todd N, Dahut W, Schlom J, Arlen PM. A phase II study of a PSA-TRICOM vaccine, and the role of GM-CSF, in patients (pts) with metastatic androgen insensitive prostate cancer (AIPC). Presented at: 2005 American Society of Clinical Oncology Prostate Cancer Symposium. Orlando, FL: February 17-19, 2005. Abstract 287.