|Dr. Ravi A. Madan||Dr. William L. Dahut|
It has been almost 3 years since the U.S. Food and Drug Administration approved sipuleucel-T, a therapeutic cancer vaccine targeting prostatic acid phosphatase, based on clinical data showing an improvement in overall survival (OS) in men with metastatic prostate cancer.1 Nonetheless, there is still uncertainty about how best to incorporate this treatment into the evolving therapeutic landscape of prostate cancer. Data from the sipuleucel-T trials and other immunotherapy studies (e.g., ipilimumab in melanoma and PSA-TRICOM in prostate cancer) suggest that it may take time for immune-based treatments to show antitumor activity.2,3
However, these studies also suggest that immune-based treatments may slow the tumor growth rate over time without leading to marked short-term tumor shrinkage (Figure), an effect that could lead to improved OS without improved time to progression (TTP, trajectory A in Figure).4,5 This is not the outcome generally seen with cytoreductive therapies, which have a transient effect on tumor growth rates (trajectory B in Figure). This mechanism of improved OS without improved short-term TTP suggests that the most prudent use of immunotherapies such as sipuleucel-T would be early in the disease process, which would allow sufficient time for any potential effect on tumor growth.
Immunotherapies in Phase III Trials in Prostate Cancer
Several ongoing phase III clinical trials may provide further insight into the clinical benefits of immunotherapy in prostate cancer. PSA-TRICOM, an off-the-shelf poxviral-based therapeutic cancer vaccine, is in phase III clinical trials that are also prospectively evaluating the vaccine’s effect on tumor growth rate (NCT01322490). In addition, two randomized, placebo-
controlled phase III trials are investigating the immune checkpoint inhibitor ipilimumab in metastatic castration-resistant prostate cancer (mCRPC). The first of these trials is in patients who are chemotherapy-naïve (NCT01057810). In the second study, patients previously exposed to docetaxel receive limited radiation therapy to individual bone lesions as an immune enhancer, followed by placebo or by ipilimumab (NCT00861614). OS is the primary endpoint of all of these trials.
Future Directions: Immune-Based Combination Therapies
In an evolving clinical setting where multiple immunotherapeutic agents may be approved for the treatment of mCRPC, optimizing these therapies becomes a priority. Although combining therapies can have additive benefit, the immunologic effect of commonly used therapies in the management of prostate cancer has provided further impetus for the investigation of synergistic immune-based combination strategies. Even at sublethal doses, radiation has been shown to alter the phenotypic expression of malignant cells, up-regulating tumor antigens that can be targeted by immune cells previously activated by immunotherapy. In addition, radiation-enhanced expression of ligands such as Fas facilitates immune-mediated cell killing.6 These radiation-mediated effects provide the basis for the so-called abscopal effect, and the rationale for the post-docetaxel ipilimumab phase III trial, among other trials combining immunotherapy with definitive radiation therapy.
Androgen-deprivation therapy (ADT) can also enhance the immune response. Clinical data have demonstrated that ADT traffics T cells to the prostate and decreases immune tolerance to self-antigens overexpressed on prostate cancer cells.7,8 ADT also induces the thymus to produce naïve T cells that can be activated by immunotherapy.9 Given these effects, ADT combined with immunotherapy presents an attractive therapeutic opportunity. A recent study combining sipuleucel-T and ADT in patients with biochemical recurrence has completed accrual and results are pending (NCT01431391).
Although there are concerns about potential immunosuppressive effects of prednisone (a requisite component of abiraterone and chemotherapy in mCRPC), no clinical data have suggested that the immune effects or potential clinical benefits of sipuleucel-T are altered by subsequent prednisone-containing treatment regimens. In fact, an analysis of immune cells after 6 months of docetaxel-based therapy found no effect on immune-cell function.10 An ongoing trial investigating the sequential or concurrent use of abiraterone and prednisone with sipuleucel-T could provide clinical data that resolve these concerns (NCT01487863).
Two trials at the National Cancer Institute, one in patients with biochemical recurrence and one in chemotherapy-
naïve mCRPC, will evaluate enzalutamide alone and with PSA-TRICOM. Both studies are investigating the hypothesis that immunotherapy can slow TTP after the initial effect of a cytoreductive agent (trajectory C in Figure). If vaccines can be shown to alter tumor regrowth/TTP when combined with an antiandrogen, immunotherapy might be redefined as a companion therapy that enhances clinical benefit. Perhaps more important, if the combination enhances TTP relative to enzalutamide alone, it would alleviate concerns about the lack of a short-term biomarker of response with immune-based therapies, which has contributed to some clinicians’ reluctance to use sipuleucel-T.
Immunotherapy as Precision Medicine
The ongoing quest for personalized therapies has focused primarily on identifying specific mutations within a patient’s tumor and then targeting the associated molecular pathways with relevant targeted agents. Although there have been some significant breakthroughs, the effect of such precision strategies is often limited by the clonal evolution of cancer cells in response to the targeted agent, as well as the toxicity associated with such therapies.
“As with any new therapy, demonstrating clinical effect is only the first step. The second, and perhaps most crucial, part of the process is determining how to optimize a new therapy in clinical practice.”
— Drs. Ravi A. Madan and William L. Dahut
A significant immunotherapy-induced effect may initiate an immune response with the potential to evolve as the tumor evolves. Although therapeutic cancer vaccines such as sipuleucel-T and PSA-TRICOM target single tumor antigens, data from multiple clinical trials have demonstrated that, ultimately, the immune response may target antigens not specified in the vaccine, such as MUC-1 and CEA in prostate cancer, through a process known as “antigen cascade” or “antigen spreading.”11,12 In this phenomenon, dead or dying cancer cells in the setting of an immune response may release secondary antigens that are then processed by the activated immune system and subsequently used to target additional cancer cells. In this manner, a sustained immune response generated by an immune-stimulating therapy may identify new target antigens as clonal evolution
occurs. Thus, a sustained immune response may continually lyse cancer cells, even if subsequent generations of malignant cells are phenotypically disparate from cells initially targeted by the vaccine. Although a time lag between clonal evolution and the targeting of new antigens by immune cells may be expected, this continued effect after initial immunotherapy is consistent with a moderation of the tumor growth rate. Additional cytoreductive therapies may further contribute to this process by furnishing the immune system with more new targets from dead and dying cancer cells.
The ability to stimulate this type of precision immune response could have significant long-term clinical benefits for patients with early-stage disease, as well as for high-risk patients receiving radiation or for patients with biochemical recurrence receiving ADT. The ideal result would be slower disease growth in the years following initial treatment, perhaps limiting the need for more toxic therapies or substantially delaying clinically meaningful mCRPC.
The endeavor to initiate immunotherapy early in the disease process faces clear obstacles. First, clinical trial endpoints in this setting remain elusive, and this will be the topic of an upcoming FDA-sponsored summit at the Annual American Urological Association Meeting. Furthermore, the absence of surrogate immunologic biomarkers of response (likely a result of the complexity of the immune response and patient variability) make it difficult to design clinical trials that explore the potential tumor growth-moderating effect of immunotherapy in patients with early-stage disease recurrence or micrometastases. Despite these obstacles, clinical trials are underway to evaluate the effect of immune-based therapies on tumor growth rate, as measured by prostate-specific antigen doubling time or similar parameters. If clinical trials in mCRPC (such as the ongoing phase III PSA-TRICOM trial) can link changes in tumor growth rate to clinical outcomes, we may discover a way to evaluate such growth-rate changes in patients with micrometastatic disease, where immunotherapy may have its greatest effect.
As with any new therapy, demonstrating clinical effect is only the first step. The second, and perhaps most crucial, part of the process is determining how to optimize a new therapy in clinical practice. For immunotherapies, which may have continuous and evolving effects during a patient’s lifetime, the second step may pay significantly greater dividends than initial clinical trials have suggested.