A recurrent finding in recent large, controlled studies of immunotherapies for cancer has been improved overall survival (OS) without an improvement in median progression-free survival (PFS). This provides a hurdle for timely completion of proof-of-concept efficacy studies. This lack of improvement in PFS with eventual demonstration of improved OS may be due to the time lag between administering the immunotherapy and a clinically significant immune-mediated slowing of the tumor growth rate. Approval of the first therapeutic cancer vaccine has conferred higher priority on the effort to augment the immunologic impact of novel experimental therapeutic vaccines with other therapies. Careful preclinical studies have highlighted the ability of standard therapies to (a) kill cells in an immunologically relevant manner (immunogenic cell death) and (b) change the phenotype of surviving cells to make them more susceptible to immune-mediated recognition and killing (immunogenic modulation). This has led to rationally designed studies combining therapeutic cancer vaccines with standard therapies. These recent preclinical and clinical studies have demonstrated the host's ability to mount immune responses to vaccine despite standard therapies (e.g., chemotherapy). These combination studies provide a platform for testing the ability of combination strategies to impact more traditional phase II endpoints such as PFS. If the above hypothesis on tumor growth rate is correct, it suggests that if one could rationally combine therapeutic vaccines (associated with delayed effects) with standard therapies (associated with an early but transient decrease in tumor volume) in a manner that doesn't decrease immune responses, then one might be able to use events such as PFS to discriminate between standard-of-care and combination regimens. Data from 3 small, randomized phase II studies of standard therapy with or without vaccine support this approach. Several vaccines have been developed within the CCR in association with BN, our CRADA partner. These include Prostvac (PSA-TRICOM), which contains genes for prostate-specific antigen (PSA) and a triad of costimulatory molecules (TRICOM), and Panvac, which contains CEA, MUC-1 and TRICOM. Two combination trials in prostate cancer suggest an improvement in PFS: Quadramet with or without Prostvac vaccine (1.7 vs. 3.7 months, P = 0.035, HR 0.48) in 44 patients with disease metastatic to bone (trial results being written), and flutamide with or without Prostvac vaccine (preliminary, 108 vs. 192 days) in 41 patients with nonmetastatic castration-resistant disease (trial recently completed accrual). A breast cancer trial comparing docetaxel with or without Panvac vaccine in 48 patients with metastatic disease shows a trend favoring the combination in PFS (3.8 vs. 6.6 months, P = 0.12, HR 0.67, trial results being written). Rationally designed combination studies have the potential to significantly expedite analysis in proof-of-concept efficacy studies (phase II) and may also improve patient outcomes over standard therapy alone. A recently opened collaborative study (GMB, UOB, LTIB) is evaluating BCG with or without Panvac in patients with superficial bladder cancer who have recurrence despite prior BCG. Monoclonal antibodies have been combined with vaccines for the treatment of various tumor types. In prostate cancer, a human cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody has been tested in combination with vaccines. CTLA-4 is a T-cell surface glycoprotein that is upregulated following T-cell activation to inhibit the immune response. Its main function is to prevent autoimmunity by regulating the body's immune activity. T cells express two counteracting receptors on their cell surface: CD28 and CTLA-4. Both bind to the same ligands or costimulatory molecules on the surface of APCs (B7.1 and B7.2, also known as CD80 and CD86). Binding of these costimulatory molecules to CD28 activates T cells, while interacting with CTLA-4 inhibits T-cell stimulation. Blocking CTLA-4 with a neutralizing antibody has been shown to sustain and potentiate immune responses. We have recently completed a safety study of PROSTVAC combined with ipilimumab, which blocks negative costimulation. Up to 10 mg/kg of ipilimumab was safely administered with a vaccine that enhances positive costimulation. Immune-related adverse events were similar in proportion and grade to those previously reported with ipilimumab alone. Furthermore, while the median predicted survival was about 18 months based on a validated nomogram, actual median OS exceeded 34 months in this phase I study (recently published in Lancet Oncology). Recent clinical data on PD1 or PDL1 inhibition have accelerated interest in the field of immunotherapy. Results have suggested deep and durable clinical response. However, the proportion of patients who derive benefit from this approach as a single agent remains limited, with many studies reporting a 20%-30% objective response rate. Often, however, these responses are associated with underlying PDL1 expression at the level of the tumor. It has been demonstrated that PDL1 expression can be upregulated by IFN-gamma secreted by tumor-infiltrating lymphocytes. De novo prostate cancer expresses very little PDL1;thus, it is not surprising that anti-PD1 and anti-PDL1 antibodies have induced limited responses in these patients. However, emerging data suggest that prostate cancer therapeutic vaccines can drive activated T lymphocytes into the tumor and up regulate PDL1 expression. This could make an unresponsive tumor much more likely to respond to immune checkpoint inhibition. To explore this possibility, we have recently obtained approval from our CRADA partners Bavarian Nordic and EMD Serono for a combination study of PSA-TRICOM (developed at the CCR) and an anti-PDL1 antibody whose first-in-human dose escalation study was performed at the CCR.
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