Combining a Recombinant Cancer Vaccine with Standard Definitive Radiotherapy in Patients with Localized Prostate Cancer

Abstract

Purpose: Many patients with clinically localized prostate cancer develop biochemical failure despite excellent local therapy perhaps due to occult metastatic disease. One potential solution is the utilization of a well-tolerated systemic therapy (e.g., vaccine) in concert with local therapy. Experimental Design:We present a randomized phase II clinical trial designed to determine if a poxviral vaccine encoding prostate-specific antigen (PSA) can induce a PSA-specific T-cell response when combined with radiotherapy in patients with clinically localized prostate cancer. Thirty patients were randomized in a 2:1 ratio into vaccine plus radiotherapy or radiotherapyonly arms. Those patients in the combination arm received a ''priming'' vaccine with recombinant vaccinia (r V) PSA plus r V containing theT-cell costimulatory molecule B7.1 (r V-B7.1) followed by monthly booster vaccines with recombinant fowlpox PSA. The vaccines were given with local granulocyte-macrophage colony-stimulating factor andlow-dose systemicinterleukin-2. Standard external beam radiation therapy was given between the fourth and the sixth vaccinations. Results: Seventeen of 19 patients in the combination arm completed all eight vaccinations and 13 of these 17 patients had increases in PSA-specificTcells of at least 3-fold versus no detectable increases in the radiotherapy-only arm (P <0.0005).There was also evidence ofde novo generation of T cells to well-described prostate-associated antigens not found in the vaccine, providing indirect evidence of immune-mediated tumor killing. The vaccine was well tolerated. Conclusion:This vaccine regimen can be safely given in patients undergoing radiation therapy for localized prostate cancer, with the majority of patients generating a PSA-specific cellular immune response to vaccine.

Tetracycline-regulated intratumoral expression of interleukin-3 enhances the efficacy of radiation therapy for murine prostate cancer

“…2,[5][6][7] On the other hand, while there is evidence that RT generates 'danger' signals that might mature dendritic cells (DCs) to present tumor antigen 8,9 there is no good evidence that this occurs in the clinic and such signals may be too weak to be effective. In a recent randomized phase II clinical trial study, 10 addition of recombinant vaccine administration to standard RT in patients with clinically localized prostate cancer showed that vaccination was safe and the generation of a PSAspecific cellular immune response was enhanced following RT. We have shown in previous studies that expression of interleukin-3 (IL-3) gene within tumors can enhance the immunogenicity of even classically nonimmunogenic tumors, 11 without altering their intrinsic radiosensitivity, and this enhances the effects of radiation therapy (RT), allowing a long-term state of immunity to develop after the primary tumor regresses.…”

A Blueprint to Advance Colorectal Cancer Immunotherapies

“…The abscopal effect (when local radiotherapy is associated with regression of metastatic cancer at a distant site) has been seen in the setting of checkpoint blockade (26,27). The rationale for combining radiotherapy with immunotherapy is to induce an in situ vaccine effect, leading to antigenic spread, uptake of antigens, maturation of DCs, and activation of T cells (28). Like radiation, chemotherapy causes direct cell killing and induction of ICD (29).…”

CpG Oligodeoxynucleotides Enhance the Activities of CD8+ Cytotoxic T-Lymphocytes Generated by Combined hMUC1 Vaccination and hNIS Radioiodine Gene Therapy

“…Radiation in combination with cancer vaccines has been found to kill tumor cells effectively [12,13]. Radiation is known to kill cancer cells via its direct cytotoxic effect and via the induction of radiation-induced immune response [1,14,15].…”