Therapeutic Cancer Vaccines for Prostate Cancer Treatment
Therapeutic Cancer Vaccines for Prostate Cancer Treatment
Sipuleucel-T is a therapeutic cancer vaccine derived from a patient's own immune cells, which are manipulated ex vivo to generate this active cellular product. This agent was developed with the objective of initiating a dynamic immune response targeting prostatic acid phosphatase (PAP), which is expressed by most prostate cancer cells. In order to generate the vaccine, peripheral blood mononuclear cells are obtained from each patient via leukapheresis. Antigen-presenting cells (APCs), such as dendritic cells, collected in this process are enriched by density centrifugation, then pulsed in vitro by a PAP–granulocyte–macrophage colony-stimulating factor (GM-CSF) fusion protein. The result of this in vitro stimulation is a patient-specific, activated cellular therapy. The entire process (including leukapheresis and in vitro stimulation) is repeated three times to allow for a full course of three biweekly treatments.
In a Phase I study that demonstrated safety in patients with metastatic castration-resistant prostate cancer (mCRPC), fevers, chills, fatigue and local injection-site reactions were the most common adverse events. In a subsequent Phase I/II study in patients with nonmetastatic castration-resistant prostate cancer (n = 31), sipuleucel-T was infused at weeks 0, 4 and 8. Immune analysis indicated that 38% of patients generated an immune response (in the form of T-cell proliferation) to the PAP fusion protein, and that this response was associated with delayed disease progression. Overall, six patients had a >25% decline in prostate-specific antigen (PSA), three of whom had a >50% decline.
Given these promising preliminary findings, two Phase III placebo-controlled studies were initiated in patients with mCRPC. Randomization for both studies was 2:1 in favor of the sipuleucel-T vaccine, which was administered at weeks 0, 2 and 4. Time to progression was the primary end point of both studies. The first Phase III trial enrolled 82 patients on the sipuleucel-T arm and 45 patients on placebo. However, it failed to meet its primary end point of time to progression (which favored sipuleucel-T 16.6 vs 10 weeks; p = 0.052; hazard ratio [HR]: 1.45). Based on these findings, the second Phase III trial was closed prematurely. Again, when the data from 98 enrolled patients were evaluated, no benefit in time to progression was seen. Ultimately, however, the secondary end point of overall survival was evaluated on the initial, fully enrolled Phase III trial and demonstrated a 4.5-month improvement favoring sipuleucel-T (25.9 vs 21.4 months; p = 0.01). Since overall survival was not the primary end point of the study, the FDA recommended another Phase III study to confirm the survival advantage. This third and larger Phase III trial enrolled over 500 patients, again randomized 2:1 in favor of sipuleucel-T, and this time overall survival was the primary end point Table 1. Once again, the Phase III study demonstrated a survival benefit with the vaccine (25.8 vs 21.7 months; p = 0.032; HR: 0.78), without changes in time to progression. These results led to FDA approval of sipuleucel-T in April 2010, for patients with minimally symptomatic or asymptomatic mCRPC. Each dose of sipuleucel-T contains a minimum of 50 million autologous CD54 cells activated with PAP–GM-CSF.
Another therapeutic vaccine for prostate cancer that is in late stages of clinical trials does not require ex vivo processing of immune cells. PSA-TRICOM (PROSTVAC™), developed by the National Cancer Institute (NCI) and licensed to BN Immunotherapeutics (Mountain View, CA, USA) is a vector-based vaccine that targets PSA through the use of genetically altered poxviruses. Poxviral-based vaccines deliver transgenes for tumor-associated antigens such as PSA to APCs through cellular infection via subcutaneous injections. Once these transgenes have been processed, they are expressed on the APC surface within the MHC, leading to T-cell activation and targeted tumor-cell destruction. Poxviral-based vaccines are processed entirely within cellular cytoplasm, so there is no risk of transgenes integrating into human DNA.
A previous Phase II clinical trial demonstrated the merit of a heterologous prime–boost strategy for administering poxviral-based vaccines. In this case, vaccinia and fowlpox, two separate species of poxviruses, were tested and each was found to have merit. Vaccinia initiates a robust immune response, but can stimulate neutralizing host antibodies. Fowlpox does not replicate in humans and so does not stimulate neutralizing antibodies, but can effectively boost an immune response. An evaluation of various sequences of vaccinia and fowlpox found that the optimal schedule employed a vaccinia priming dose followed by fowlpox boosting doses. On this dosing schedule, 45.3% of patients were PSA progression-free at 19.1 months and 78.1% demonstrated clinical progression-free survival. This same schedule has been employed in subsequent trials of PSA-TRICOM.
PSA-TRICOM also includes transgenes for three T-cell costimulatory molecules, which results in enhanced T-cell activation. A Phase I study in patients with mCRPC demonstrated that PSA-TRICOM was well tolerated, with common side effects of mild injection-site reactions, fever and influenza-like symptoms. Four of six evaluable patients demonstrated an increase in the number of PSA-specific T cells after treatment with the vaccine. In addition, nine out of 15 patients had decreases in PSA velocity.
Two Phase II studies with PSA-TRICOM have been completed in mCRPC patients that dosed the vaccine at monthly intervals until disease progression. The larger of the two studies (n = 125) was a placebo-controlled, multicenter trial in patients with a Gleason score of ≤7 and no evidence of visceral metastasis. Randomization was 2:1 in favor of PSA-TRICOM, which was administered via monthly subcutaneous injections. Similar to the sipuleucel-T trials, this study showed no changes in time to progression (the primary end point); however, median overall survival was 25.1 months in the vaccine arm compared with 16.6 months in the control arm, in which patients were given wild-type poxvirus (p = 0.0061; HR: 0.56).
Another Phase II study of PSA-TRICOM was a single-arm trial at the National Cancer Institute (n = 32), which treated patients with mCRPC regardless of Gleason score. The median overall survival was 26.6 months, which was similar to the findings of both the larger PSA-TRICOM trial and the sipuleucel-T trials. Immunologic analysis indicated that 13 out of 29 evaluable patients had a >twofold increase in PSA-specific T cells. Patients with the greatest immune response showed a trend toward improved overall survival (p = 0.055).
Results of Vaccine Clinical Trials
Sipuleucel-T
Sipuleucel-T is a therapeutic cancer vaccine derived from a patient's own immune cells, which are manipulated ex vivo to generate this active cellular product. This agent was developed with the objective of initiating a dynamic immune response targeting prostatic acid phosphatase (PAP), which is expressed by most prostate cancer cells. In order to generate the vaccine, peripheral blood mononuclear cells are obtained from each patient via leukapheresis. Antigen-presenting cells (APCs), such as dendritic cells, collected in this process are enriched by density centrifugation, then pulsed in vitro by a PAP–granulocyte–macrophage colony-stimulating factor (GM-CSF) fusion protein. The result of this in vitro stimulation is a patient-specific, activated cellular therapy. The entire process (including leukapheresis and in vitro stimulation) is repeated three times to allow for a full course of three biweekly treatments.
In a Phase I study that demonstrated safety in patients with metastatic castration-resistant prostate cancer (mCRPC), fevers, chills, fatigue and local injection-site reactions were the most common adverse events. In a subsequent Phase I/II study in patients with nonmetastatic castration-resistant prostate cancer (n = 31), sipuleucel-T was infused at weeks 0, 4 and 8. Immune analysis indicated that 38% of patients generated an immune response (in the form of T-cell proliferation) to the PAP fusion protein, and that this response was associated with delayed disease progression. Overall, six patients had a >25% decline in prostate-specific antigen (PSA), three of whom had a >50% decline.
Given these promising preliminary findings, two Phase III placebo-controlled studies were initiated in patients with mCRPC. Randomization for both studies was 2:1 in favor of the sipuleucel-T vaccine, which was administered at weeks 0, 2 and 4. Time to progression was the primary end point of both studies. The first Phase III trial enrolled 82 patients on the sipuleucel-T arm and 45 patients on placebo. However, it failed to meet its primary end point of time to progression (which favored sipuleucel-T 16.6 vs 10 weeks; p = 0.052; hazard ratio [HR]: 1.45). Based on these findings, the second Phase III trial was closed prematurely. Again, when the data from 98 enrolled patients were evaluated, no benefit in time to progression was seen. Ultimately, however, the secondary end point of overall survival was evaluated on the initial, fully enrolled Phase III trial and demonstrated a 4.5-month improvement favoring sipuleucel-T (25.9 vs 21.4 months; p = 0.01). Since overall survival was not the primary end point of the study, the FDA recommended another Phase III study to confirm the survival advantage. This third and larger Phase III trial enrolled over 500 patients, again randomized 2:1 in favor of sipuleucel-T, and this time overall survival was the primary end point Table 1. Once again, the Phase III study demonstrated a survival benefit with the vaccine (25.8 vs 21.7 months; p = 0.032; HR: 0.78), without changes in time to progression. These results led to FDA approval of sipuleucel-T in April 2010, for patients with minimally symptomatic or asymptomatic mCRPC. Each dose of sipuleucel-T contains a minimum of 50 million autologous CD54 cells activated with PAP–GM-CSF.
PSA-TRICOM
Another therapeutic vaccine for prostate cancer that is in late stages of clinical trials does not require ex vivo processing of immune cells. PSA-TRICOM (PROSTVAC™), developed by the National Cancer Institute (NCI) and licensed to BN Immunotherapeutics (Mountain View, CA, USA) is a vector-based vaccine that targets PSA through the use of genetically altered poxviruses. Poxviral-based vaccines deliver transgenes for tumor-associated antigens such as PSA to APCs through cellular infection via subcutaneous injections. Once these transgenes have been processed, they are expressed on the APC surface within the MHC, leading to T-cell activation and targeted tumor-cell destruction. Poxviral-based vaccines are processed entirely within cellular cytoplasm, so there is no risk of transgenes integrating into human DNA.
A previous Phase II clinical trial demonstrated the merit of a heterologous prime–boost strategy for administering poxviral-based vaccines. In this case, vaccinia and fowlpox, two separate species of poxviruses, were tested and each was found to have merit. Vaccinia initiates a robust immune response, but can stimulate neutralizing host antibodies. Fowlpox does not replicate in humans and so does not stimulate neutralizing antibodies, but can effectively boost an immune response. An evaluation of various sequences of vaccinia and fowlpox found that the optimal schedule employed a vaccinia priming dose followed by fowlpox boosting doses. On this dosing schedule, 45.3% of patients were PSA progression-free at 19.1 months and 78.1% demonstrated clinical progression-free survival. This same schedule has been employed in subsequent trials of PSA-TRICOM.
PSA-TRICOM also includes transgenes for three T-cell costimulatory molecules, which results in enhanced T-cell activation. A Phase I study in patients with mCRPC demonstrated that PSA-TRICOM was well tolerated, with common side effects of mild injection-site reactions, fever and influenza-like symptoms. Four of six evaluable patients demonstrated an increase in the number of PSA-specific T cells after treatment with the vaccine. In addition, nine out of 15 patients had decreases in PSA velocity.
Two Phase II studies with PSA-TRICOM have been completed in mCRPC patients that dosed the vaccine at monthly intervals until disease progression. The larger of the two studies (n = 125) was a placebo-controlled, multicenter trial in patients with a Gleason score of ≤7 and no evidence of visceral metastasis. Randomization was 2:1 in favor of PSA-TRICOM, which was administered via monthly subcutaneous injections. Similar to the sipuleucel-T trials, this study showed no changes in time to progression (the primary end point); however, median overall survival was 25.1 months in the vaccine arm compared with 16.6 months in the control arm, in which patients were given wild-type poxvirus (p = 0.0061; HR: 0.56).
Another Phase II study of PSA-TRICOM was a single-arm trial at the National Cancer Institute (n = 32), which treated patients with mCRPC regardless of Gleason score. The median overall survival was 26.6 months, which was similar to the findings of both the larger PSA-TRICOM trial and the sipuleucel-T trials. Immunologic analysis indicated that 13 out of 29 evaluable patients had a >twofold increase in PSA-specific T cells. Patients with the greatest immune response showed a trend toward improved overall survival (p = 0.055).
