BERKELEY, CA (UroToday.com) - The potential role of immunotherapy in the clinical management of malignancies has been debated for decades by researchers and medical oncologists.
The discussion has been taken to a more practical level with the FDA approval of sipuleucel-T, the first personalized immunotherapy that activates the patient’s own immune cells to target and attack prostate cancer cells. Sipuleucel-T is an autologous cellular immunotherapy indicated for treatment of patients with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC). Treatment with this therapeutic cancer vaccine has shown improved survival, but no change in time to disease progression, in men with mCRPC. As a first-in-class therapy, it has been met with both great excitement and controversy.
The goal of immunotherapy is to utilize the immune system’s ability to recognize and destroy cancer cells. Over the years, three main treatment strategies have been investigated: 1) the use of cytokines or chemokines to activate a non-specific immune response; 2) the selective removal of immune checkpoint inhibitors; and 3) the use of therapeutic vaccines.
Different strategies for optimizing therapeutic cancer vaccines:
- Immune-based therapies early in the disease process – the vaccines have limited toxicity, therefore it may be feasible to start therapy early in the disease process with a goal of modulating long-term growth patterns and potentially improving survival significantly.
- Combination therapy – vaccines used in combination with immune-enhancing therapies may result in more immediate cytotoxic effects and a slower growth rate due to a sustained immunologic effect.
- Immune-modulating therapies – some therapies (e.g., sunitinib) may alter the immune regulatory mechanisms that can suppress a vaccine-induced immune response. Therefore, combining these therapies with vaccines may result in enhanced immune responses.
In the case of sipuleucel-T, antigen-presenting cells (APCs) are used to initiate a diverse, lasting, tumor-specific immune response. In order to achieve this, autologous peripheral-blood mononuclear cells (PBMCs) are isolated via leukapheresis and sent to a central facility where APCs are activated ex vivo with a recombinant fusion protein. This recombinant fusion protein consists of a prostate antigen, prostatic acid phosphatase (PAP) that is fused to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune-cell activator. The resulting cell product (sipuleucel-T) is reinfused into the patient.
| The ultimate role of immunotherapy may not be to take the place of standard therapies, but rather to work in combination with them to maximize clinical benefit for patients. |
After two small phase III trials with sipuleucel-T in minimally symptomatic mCRPC, no change in time to progression (primary endpoint in both studies) was shown, but a preplanned secondary analysis suggested an improvement in overall survival. This outcome resulted in the initiation of a third larger trial with survival as the primary endpoint. The patient population in this trial was essentially the same as in the previous two trials, i.e. patients with good functional status and asymptomatic or minimally symptomatic mCRPC. The results of this trial demonstrated an improvement in overall survival in the sipuleucel-T group vs. the placebo group (25.8 months vs. 21.7 months; p=0.032), representing a 4.1- month improvement in median survival. This led to FDA approval of sipuleucel-T, representing the first approval of a therapeutic cancer vaccine. Again, no change in time to disease progression was seen. In spite of its status as a first-in-class agent and its minimal toxicity, sipuleucel-T has not yet been widely embraced by physicians who treat prostate cancer. Together with practical issues involving logistics, cost, and reimbursement, the lack of early markers of therapeutic benefit has been a major concern. Sipuleucel-T has not shown an ability to shrink tumor or decrease PSA levels in most patients, like standard cytotoxic therapies or hormonal therapies have been able to show. However, closer analysis shows that two other immune-based therapies also have shown improvement in overall survival without near-term changes in tumor characteristics.
PSA-TRICOM is another therapeutic cancer vaccine now in phase III trials in minimally symptomatic mCRPC. As with sipuleucel-T, no difference was seen in time to disease progression, but significant improvement in overall survival was noted in the PSA-TRICOM group compared to the placebo group (25.1 months vs. 16.6 months; p=0.0061). This represents an 8.5-month improvement in median survival.
Similarly, ipilimumab has shown delayed effects in metastatic melanoma. This monoclonal antibody serves as an immune checkpoint inhibitor. A phase III study of ipilimumab in melanoma showed no significant difference in median progression-free survival, but overall survival favored the ipilimumab groups (10.0 months and 10.1 months) over the active control group (6.4 months; p < 0.001 and p=0.003 respectively).
Together, these data suggest that a delay in clinical impact seen with the use of modern immunotherapeutics in metastatic cancer may not be something associated only with sipuleucel-T, but rather an apparent class effect of emerging immunologic agents associated with this type of therapy. Immune-based therapies work indirectly on the immune system, which in turn targets the tumor, and this may take time and may partially explain why short-term changes in disease course may not demonstrate an impact of therapy. Their impact on tumor is more likely to be a moderation in growth rather than dramatic shrinkage, based on the nature of immune responses. Even though slowing a tumor’s growth may not seem as important as reducing its mass, it may ultimately have a greater impact on outcome, because an immune response is likely to be maintained long after treatment termination, unlike cytotoxic therapies , whose transient impact on tumor size is limited to the treatment period.
This change in tumor-growth kinetics was initially suggested by a retrospective analysis of five NCI trials in mCRPC over the past decade. Four trials involved cytoreductive therapy and one involved the investigational vaccine PSA-TRICOM. A mathematical model was used to predict disease mortality (model developed and used in other cancers by using disease-appropriate markers); PSA values were used to evaluate tumor growth kinetics and to predict death. Patients who were initially treated with chemotherapy-based regimens showed decreases in tumor burden, but once treatment was discontinued, the tumor returned to pretreatment rates and time to death was predictable, along this trajectory. In the trial with PSA-TRICOM, the patients showed little measurable change in the rate of tumor growth while in the trial, but death occurred well beyond the predicted time point, based on the off-treatment growth rate. This data suggest a slowing of tumor growth rate that may ultimately have prolonged the survival in the patients treated with vaccine.
The results of early trials support the hypothesis that therapeutic cancer vaccines can alter tumor growth rate. Further randomized prospective trials, with growth rate kinetics as a primary end point, are required, and these trials also need to link changes in growth-rate kinetics to a relevant and FDA-accepted clinical outcome. However, it is difficult to conduct these trials in prostate cancer when survival is the primary endpoint because this requires a follow-up of nearly 10 years. Another approach to capitalize on the ability of therapeutic cancer vaccines to alter the growth rate of tumors would involve treatments that combine vaccine with standard therapeutics. Radiation, ADT, and chemotherapy could all work in combination with therapeutic cancer vaccines to enhance clinical outcomes via numerous mechanisms.
An evolving strategy: The combination of immunotherapy with cytoreductive therapy
An ideal approach may be to combine a cancer vaccine with a cytoreductive therapy, such as chemotherapy and ADT in prostate cancer. The potential implications are twofold: 1) cytoreductive therapy buys time (perhaps 2-3 months) necessary to initiate an immune response, and 2) when the cytoreductive therapy has debulked the tumor, vaccine could be administered with the goal of altering the growth rate of the tumor. In the end, this could lead to a smaller tumor growing at a slower rate. It is likely that this combination would have a more significant impact on survival than either the transient reduction in tumor volume from cytoreductive therapy, or the altered growth kinetics from a vaccine, would have alone.
In addition, a scientific rationale exists for the combination of these therapies based on their potential to further enhance immune responses. ADT has several mechanisms for enhancing an anti-prostate cancer response and the combination of ADT plus a vaccine have shown promising results in clinical trials. Those trials suggested a benefit in patients who received both therapies. With the arrival of modern androgen receptor antagonists (ARA) such as MDV3100, previous trials combining vaccines and older ARAs have become more important, but more data from larger randomized trials are also required.
The primary chemotherapy used in patients with mCRPC is docetaxel. A phase II clinical trial in mCRPC patients demonstrated that a combination of docetaxel and vaccine generated the same magnitude of T-cell-specific immune responses as vaccine alone. In addition, a preclinical trial showed that vaccine plus docetaxel enhanced T-cell responses and antitumor activity compared with either treatment alone.
In a clinical trial that combined vaccine with standard definitive radiation therapy in newly diagnosed patients with prostate cancer, a significantly enhanced prostate cancer-specific immune response was shown in the patients treated with vaccine, plus radiation, compared with those who received radiation alone. An on-going phase III clinical trial combining ipilimumab with radiation is further investigating this in mCRPC. If vaccines can be combined with radiation in newly diagnosed prostate cancer patients, the immune response generated from this may have sustained impact on tumor growth rate for the 20% to 40% of patients who develop recurrent disease, and may even significantly delay symptomatic disease progression.
Although immune-based combinations may result in a more immediate clinical impact and avoid the need to develop intermediate markers of response, the challenge of identifying a mechanism of action remains. Much of the skepticism regarding this emerging class of therapy is fueled by the apparent lack of understanding of this mechanism. To address this, comprehensive immune monitoring is a large component of many ongoing clinical trials.
Biotechnological advances in the past decades have provided researchers with the techniques needed to monitor antigen-specific immune responses, but assay and patient variability has prevented these techniques from being developed into surrogate markers of immune response.
Perhaps a more relevant confounding variable is the discrepancies among the patients themselves, and the immune response activated by immune therapies may manifest differently from patient to patient. Therefore, we have to accept the very real possibility that standardized biomarkers of immune response remain elusive and impractical due to the variability among patients.
The focus of future studies will be on optimizing vaccine strategies, perhaps through deployment in combination with cytotoxic therapies, leading to standard measures of improvement, such as time to progression. Long-range studies could also be designed to evaluate the effect of vaccine on tumor growth rate and overall survival, with the goal of validating short-term growth rates as an indicator of response. Thus, while sipuleucel-T has set in motion a revolution in cancer treatment, future strategies, along with next-generation immune-based treatments, will cement its legacy.
The ultimate role of immunotherapy may not be to take the place of standard therapies, but rather to work in combination with them to maximize clinical benefit for patients.
References:
Ravi A. Madan, Thomas Schwaab and James L. Gulley. Strategies for Optimizing the Clinical Impact of Immunotherapeutic Agents Such as Sipuleucel-T in Prostate Cancer. J Natl Compr Canc Netw 2012; 10:1505-1512
Philip W. Kantoff, et al. (for the IMPACT Study Investigators). Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. N Engl J Med 2010; 363:411-22
Written by Anna Forsberg, medical director for UroToday.com. Anna received a BSc in zoology from Louisiana State University, and a BSc in biomedicine and MSc in clinical drug development from Uppsala University in Sweden. She has worked almost 20 years in the global pharmaceutical and medical device world, involved with clinical research management and as a Medical Science Liaison (MSL) before joining UroToday as Medical Director. Her focus in clinical research and as a MSL has mainly been in the fields of urology and oncology.
