Clinical trials employing cancer vaccine combination therapies

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Much of the focus of new therapies for cancer has shifted in the last decade to include immunotherapy. This is in part due to the rapid, profound and durable responses seen with immune checkpoint inhibitors. However, these important clinical results are only seen in a subset of patients, ones with and underlying immune recognition of the tumor. Data from Dr. Gulley's clinical trials has suggested that therapeutic vaccines can efficiently generate immune recognition and activation against targets present in the vaccine and found in tumor cells (multiple publications). In addition, there is an increased infiltrate following vaccine (JITC 2020). However, this anti-tumor immune response may not be sufficient to generate an improvement in clinical outcome for the patient without providing for adequate effector functionality within the tumor microenvironment. There are multiple immune checkpoints that are engaged on immune activation. CCR preclinical studies suggested synergy of vaccine with CTLA4 blockade. Dr. Gulley was the PI of one of the first studies combining a CCR developed vaccine (PSA-TRICOM) along with ipilimumab, an anti-CTLA4 antibody. Up to 10 mg/kg of ipilimumab was safely administered with PSA-TRICOM. 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. This also compares favorably to OS data of ipilimumab alone, however a randomized study would be required to validate these hypothesis generating findings. Recent clinical data on PD1 or PDL1 inhibition have accelerated interest in the field of immunotherapy. Dr. Gulley served as the coordinating PI of a phase I dose-escalation study of the only anti-PDL1 antibody designed to not only antagonize PDL1, but to initiate antibody mediated cellular cytotoxicity (ADCC). This first-in-human international study of this agent sponsored by our CRADA partner, EMD-Serono, enrolled 130 patients at the NIH Clinical Center and has demonstrated dramatic prolonged responses seen in a variety of cancers including lung cancer, thymic epithelial malignancies, mesothelioma, bladder cancer and ovarian cancer. Our data also demonstrated no impact of ADCC on immune cells which can also express PDL1 (albeit often at lower levels than tumor cells). Based on this clinical data the FDA approved avelumab for use in patients with bladder cancer. This data was also used in part to approve avelumab for Merkel Cell Carcinoma, and subsequently for 2 more indications (in Renal Cell Carcinoma in combination with axitinib and in 2020 the approval in the switch maintenance setting in bladder cancer). However, immune checkpoint inhibition requires an underlying anti-tumor immune response that it can unleash. In prostate cancer, the level of activated immune cells within the prostate is limited. Thus, combining vaccine with PDL1 blockade is a rational immunotherapeutic approach. We now have multiple ongoing studies in the CCR looking at vaccine with immune checkpoint inhibition. One study combining vaccine with immune checkpoint inhibitor has shown evidence of sustained 90% PSA declines in 2 of 12 patients associated with objective responses (2 CRs) with one patient remaining on study for over 3 years and the other in ongoing CR for about 4 years. Thus, it is likely that generating an immune recognition / response by specific therapeutics such as a vaccine is necessary but perhaps not sufficient for tumors like prostate cancer where there is little or no evidence of immune recognition. We also have recently opened a first-in-human, first-in-class anti-PDL1/TGF Beta Trap agent (M7824) with initial data published in 2019 demonstrating safety and preliminary evidence of activity (including PRs and a CR in the first 19 patients tested). The activity appears to be increased in HPV associated cancers (about 30% ORR) and in non-small cell lung cancer (about 28% ORR) compared to PD-1 or PDL-1 inhibition alone (JITC 2021). This study has opened the door for multiple combination therapy studies utilizing M7824 to block two important negative regulatory mechanisms that dampen an effective anti-cancer immune response. These ongoing studies will also have built in biopsies and other correlative studies to analyze the impact of the combined therapy on the tumor microenvironment. Dr. Gulley and team also have multiple studies combining modalities to initiate an immune response (vaccine or tumor targeted cytokine) along with immune checkpoint inhibition and / or TGB-beta inhibition, cytokine, IDO inhibition or small molecule inhibitors (JITC 2018, ESMO 2020). Preliminary data suggests that a combination of vaccine (pox viral vectors encoding genes for 3 T-cell costimulatory molecules and brachyury), IL-15 (N-803), and bintrafusp alfa (an anti-PDL1 antibody that sequesters TGF-beta, also known as M7824) have led to sustained deep PSA declines in 6 of 13 patients tested to date with objective responses by RECIST in the 2 of 6 patients with PSA responses who had disease measurable by RECIST. This could not be explained by microsattelite status in these patients and is a confirmation that approaches that generate sufficient numbers of highly functional immune cells (with vaccine and IL15) and allow them to work in the tumor micro-environment (M7824), may lead to traditionally immune unresponsive cancers being able to respond. Additional enrollment is ongoing to further characterize the clinical activity and mechanism of this activity. Additional studies with multiple experimental IO agents are ongoing in a variety of diseases.