Checkpoint Inhibitors In Melanoma Research Articles

Abstract A032: Using oncolytic polio expressing tumor as a cancer vaccine

Abstract Background: The recent clinical success of immune checkpoint inhibitors in melanoma revealed the therapeutic potential of an anti-tumor T cell response. Previous studies using peptide vaccines to elicit anti tumor T cell response have been limited in efficacy. We have discovered that an oncolytic poliovirus leads to persistent IFN dominant activation of antigen presenting cells. Based upon these findings, we propose to use a recombinant poliovirus (PVS-RIPO) expressing tumor antigens to activate antigen presenting cells and elicit an anti tumor T cell response. PVS-RIPO is the live attenuated vaccine (SABIN) type 1 containing a foreign human rhinovirus IRES. Preliminary studies in our lab showed that PVS-RIPO is a potent human dendritic cell and CD8 T cell activator. In addition, PVS-RIPO has recently achieved breakthrough status following a very promising phase I clinical trial targeting recurrent glioblastoma (GBM). The efficacy of PVS-RIPO against GBM is thought to be mediated mainly by an anti-tumor CD8 T cells response. The potent activation of dendritic cells as well as the promising results of the phase I clinical trial makes PVS-RIPO a prime candidate for use as a therapeutic tumor vaccine. The PVS-RIPO vector technology can be adapted to multiple tumor mutations, we are planning to target 2 glioma mutations at this stage: IDH1R132H and EGFRviii mutations. IDH1R132H is a point mutation in the enzyme isocitrate dehydrogenase 1, the mutation is present at high frequency (>70%) in low grade glioma. EGFRviii is a deletion in exon 2-7 of the EGFR gene, it is present in 67% of patients with GBM. Results: Adjuvancy of PVS-RIPO We first tested the immune adjuvancy of PVS-RIPO in an in vitro human system. PVS-RIPO was found to sub lethally infect and activate dendritic cells leading to pro inflammatory cytokine production. In addition, dendritic cell incubated with tumor cell lysate, PVS-RIPO and autologous T cells produced an anti tumor CD8 T cell response. Designing stable PVS-RIPO Vectors Previous attempts to use poliovirus as a vaccine vector were unsuccessful because of its notorious genetic instability. Our lab has developed a novel strategy to generate stable poliovirus vectors: we use the relative genetic plasticity of the IRES (the dispensable stem-loop Domain VI) to encode tumor antigens. We have successfully made stable PVS-RIPO vectors expressing EGFRviii and IDH1R132H antigens. Mouse models to study efficiency of vaccine in vivo Because PVS-RIPO has a rhinovirus IRES, it is incompetent in mouse cells and first had to be adapted for mouse competency. Through murine cell passaging, we have successfully generated a mouse adapted PVS-RIPO virus (mPVS-RIPO) with 5 point mutations in the IRES. We also generated 3 different transgenic (expressing the human poliovirus receptor, CD155) mouse tumor models: 1. Chemically induced model: CT2A-CD155 (C57BL/6-CD155), 2. Genetic model: Neuro Stem Cell-P53fl/fl-mPDGFB-CD155 (C57BL/6-CD155) and 3. Spontaneous tumor model: SMA560-CD155 (VM/DK-CD155). Conclusion: Here we have put together all the required tools to test the antitumor efficacy of a PVS-RIPO vector vaccine in vivo. Given that PVS-RIPO has some replication competence in muscle cells and also in tumor cells, we are planning to administer the mPVS-RIPO vector intramuscularly as well as intratumorally in mice and monitor its anti tumor efficacy. Citation Format: M Mubeen Mosaheb, Elena Dobrikova, Michael C. Brown, Christopher Pirozzi, Vidyalakshmi Chandramohan, Eda Holl, Smita Nair, Matthias Gromeier. Using oncolytic polio expressing tumor as a cancer vaccine [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A032.

Future perspectives in cancer immunotherapy.

The advent of immunotherapy has transformed the treatment paradigm of several solid tumors and is expected to influence the therapeutic algorithm even more in the future following the results of numerous ongoing clinical trials in a wide range of malignancies. Exploiting the anti-cancer effect of the immune system with the use of vaccines, viral vectors, and more lately with immune check-point inhibitors and chimeric antigen receptor modification, has been proven a successful therapeutic strategy in a broad spectrum of tumors. In particular, immune check-point inhibition in melanoma, non-small-cell lung cancer and renal cancer, peptide vaccination in prostate cancer and glioblastoma, and oncolytic immunotherapy in melanoma are well-established therapeutic modalities that have obtained approval by regulatory authorities and are already in clinical use. A large number of ongoing clinical trials involving thousands of patients are currently seeking to define the appropriate tumor type, therapeutic setting, treatment combination and patient populations in order to maximize clinical benefit from immunotherapeutic agents. In this context, identification of the patients whose tumors are most likely to respond to immunotherapy by the use of appropriate biomarkers will be crucial for the optimal implementation of immunotherapy into the therapeutic armamentarium.

The integration of radiation therapy and immunotherapy in melanoma management

Melanoma has long been considered an “immunologic” malignancy because of numerous reports of spontaneous regression as well as abscopal phenomena along with its relative responsiveness to cancer immunotherapy. Over the past few years, there has been a resurgence of interest in cancer immunotherapy with particular focus on melanoma. Many new immunotherapeutic interventions have arisen, some with notable clinical efficacy. One such example is the current generation of checkpoint inhibitors. In this article, we shall review the recent data on checkpoint inhibition in melanoma along with a brief review of other immunotherapeutic approaches, including the encouraging and expanding role of radiation therapy in integrated immunotherapy.

Reporter nanoparticle that monitors its anticancer efficacy in real time

The ability to monitor the efficacy of an anticancer treatment in real time can have a critical effect on the outcome. Currently, clinical readouts of efficacy rely on indirect or anatomic measurements, which occur over prolonged time scales postchemotherapy or postimmunotherapy and may not be concordant with the actual effect. Here we describe the biology-inspired engineering of a simple 2-in-1 reporter nanoparticle that not only delivers a cytotoxic or an immunotherapy payload to the tumor but also reports back on the efficacy in real time. The reporter nanoparticles are engineered from a novel two-staged stimuli-responsive polymeric material with an optimal ratio of an enzyme-cleavable drug or immunotherapy (effector elements) and a drug function-activatable reporter element. The spatiotemporally constrained delivery of the effector and the reporter elements in a single nanoparticle produces maximum signal enhancement due to the availability of the reporter element in the same cell as the drug, thereby effectively capturing the temporal apoptosis process. Using chemotherapy-sensitive and chemotherapy-resistant tumors in vivo, we show that the reporter nanoparticles can provide a real-time noninvasive readout of tumor response to chemotherapy. The reporter nanoparticle can also monitor the efficacy of immune checkpoint inhibition in melanoma. The self-reporting capability, for the first time to our knowledge, captures an anticancer nanoparticle in action in vivo.

The Future of Melanoma Immunotherapy

The resurgence of immunotherapy in melanoma has led to impressive gains in therapeutic outcome. Yet we remain limited in our ability to predict response, toxicity, and prognosis. In this brief review, we outline pressing questions for clinical investigation using the backbone of checkpoint inhibition in melanoma. Future trials must also evaluate strategies to improve the economics of melanoma therapy.

Immune checkpoint inhibitors in melanoma.

The potential to harness the power of the immune system and effectively treat patients with metastatic melanoma is finally being realized with the advent of immune checkpoint inhibitors. These new therapies herald a new era in the treatment of melanoma with the potential to produce very durable responses and possible cure for a subset of patients, though bring with them challenges including novel toxicities and nonconventional response patterns. This article reviews the currently available immune checkpoint inhibitors, potential biomarkers to predict response and promising investigational approaches including combination therapies.

Combining active immunotherapy and immune checkpoint inhibitors in prostate cancer.

172 Background: Results of recent clinical trials have intensified interest in immunotherapy in oncology. A number of cancer immunotherapies have been approved recently, while others are in late stage clinical development. The poxvirus-based active immunotherapy, PROSTVAC is generally well tolerated and is currently being evaluated in a global Phase 3 randomized, placebo-controlled trial. Ipilimumab, an approved immune checkpoint inhibitor in melanoma, is also being evaluated in a Phase 3 trial in chemo-naïve mCRPC. Methods: Results of two Phase 2 trials in men with mCRPC who were treated with PROSTVAC alone were compared with results from a Phase 1 combination study in mCRPC patients treated with PROSTVAC plus escalating doses of ipilimumab. Patients were enrolled in the Phase 1 combination study when docetaxel was the only FDA-approved mCRPC treatment that improved overall survival (OS). Results: In a multicenter Phase 2 trial, 125 men were randomized 2:1 to receive PROSTVAC or placebo. Patients treated with PROSTVAC had improved OS compared to placebo (25.1 vs 16.6 months; HR 0.56; 95% CI 0.37-0.85).Similar data was seen in a second phase 2 trial of PROSTVAC, where 32 patients with mCRPC had a median OS of 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). In a Phase 1 combination study of 30 mCRPC patients with similar baseline characteristics (predicted median OS of 18.5 months), patients were treated with PROSTVAC plus escalating doses of ipilimumab. The observed median OS was 31.3 months for all dose cohorts and 37.2 months for patients treated at 10 mg/kg based on updated overall survival data. Furthermore, there appears to be a tail on the curve with approximately 20% of patients at 10 mg/kg alive at 80 months. Conclusions: The comparison of data from three independent trials of PROSTVAC active immunotherapy in three similar patient populations provides hypothesis-generating data that the addition of an immune checkpoint inhibitor may have a positive effect on overall survival through a potential synergy in mechanism of action. The updated long term survival data is further evidence of improved OS with PROSTVAC. Future randomized trials are being planned to prospectively evaluate this hypothesis. Clinical trial information: NCT00113984.

IT-26 * IDENTIFICATION OF PSEUDO-PROGRESSION IN NEW DIAGNOSED GLIOBLASTOMA (GBM) IN A RANDOMIZED PHASE 2 OF ICT-107: MRI AND PATHOLOGY CORRELATION

BACKGROUND: Previously reports of pseudo-progression in patients with brain tumor after therapeutic vaccines in pediatric and adult glioma (Pollack, JCO online on June 2, 2014 and Okada, JCO Jan 20, 2011; 29: 330-336) demonstrated that RANO criteria for tumor progression may not be adequate for immunotherapy trials. Similar observations were also seen in other checkpoint inhibitor in melanoma and NSLSC. METHODS: We identified 2 patients, who developed tumor progression by RANO criteria, underwent surgery following enrollment in a phase 2 randomized ICT-107 (an autologous vaccine consisting of patient dendritic cells pulsed with peptides from AIM-2, TRP-2, HER2/neu, IL-13Ra2, gp100, MAGE1) after radiation and Temozolomide (TMZ). RESULTS: The first case is a 69 years old Chinese male, who underwent 1st surgery of gross total resection right occipital GBM on 10/26/2011. Subsequently he received 19 cycles of TMZ and 9 vaccines/placebo. MRI from 7/2/2013 showed enhancement surrounding surgical cavity. After 2nd surgery, pathology showed only rare residual tumor cells with macrophages and positive CD 8 cells. He continued on this vaccine program and MRI showed more progression with finger-like extension into parietal lobe 4 months later. The 3rd surgery also showed extensive reactive changes with no active tumor cells. For 2nd case, a 62 years old male, who underwent first surgery on 7/11/2011 of right temporal lobe, developed 2 areas of enhancement after 6 cycles of TMZ and 7 vaccines/placebo on 4/18/2012. With 2nd surgery, pathology showed reactive gliosis without active tumor. The subject continued in this trial. CONCLUSION: Pseudo-progression was confirmed by pathology in these 2 patients at 20 and 9 months which were delayed comparing to pseudo-progression observed in patients treated with concurrent XRT/TMZ (3-6 months). Future iRANO criteria development is essential for immunotherapy trials. Accurately identifying and managing such patients is necessary to avoid premature termination of therapy.