Ann W. Silk

Into the clinic: Talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy

With the recent regulatory approval of Talimogene laherparepvec (T-VEC) for the treatment of advanced of melanoma in the United States, Europe and Australia, oncolytic virus immunotherapy has earned its place in the clinic. However, the adoption of T-VEC by the U.S. oncology community has been slow, and so far has been largely limited to specialized cancer centers. Limiting factors include the intratumoral route of administration, which is unfamiliar to medical oncologists, biosafety concerns related to the use of a live virus in the clinic, and the explosion of other therapeutic strategies now available for the treatment of advanced melanoma. Herein, we review the development of T-VEC, and suggest how it fits into the in the current clinical treatment paradigm, and provide pearls for drug preparation, administration, and monitoring of response to therapy.

Clinical Management of Multiple Melanoma Brain Metastases: A Systematic Review

IMPORTANCE The treatment of multiple brain metastases (MBM) from melanoma is controversial and includes surgical resection, stereotactic radiosurgery (SRS), and whole-brain radiation therapy (WBRT). Several new classes of agents have revolutionized the treatment of metastatic melanoma, allowing some subsets of patients to have long-term survival. Given this, management of MBM from melanoma is continually evolving. OBJECTIVE To review the current evidence regarding the treatment of MBM from melanoma. EVIDENCE REVIEW The PubMed database was searched using combinations of search terms and synonyms for melanoma, brain metastases, radiation, chemotherapy, immunotherapy, and targeted therapy published between January 1, 1995, and January 1, 2015. Articles were selected for inclusion on the basis of targeted keyword searches, manual review of bibliographies, and whether the article was a clinical trial, large observational study, or retrospective study focusing on melanoma brain metastases. Of 2243 articles initially identified, 110 were selected for full review. Of these, the most pertinent 73 articles were included. FINDINGS Patients with newly diagnosed MBM can be treated with various modalities, either alone or in combination. Level 1 evidence supports the use of SRS alone, WBRT, and SRS with WBRT. Although the addition of WBRT to SRS improves the overall brain relapse rate, WBRT has no significant impact on overall survival and has detrimental neurocognitive outcomes. Cytotoxic chemotherapy has largely been ineffective; targeted therapies and immunotherapies have been reported to have high response rates and deserve further attention in larger clinical trials. Further studies are needed to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. CONCLUSIONS AND RELEVANCE At this time, the standard management for patients with MBM from melanoma includes SRS, WBRT, or a combination of both. Emerging data exist to support the notion that SRS in combination with targeted therapies or immune therapy may obviate the need for WBRT; prospective studies are required to fully evaluate the efficacy of these novel regimens in combination with radiation therapy.

Biomarkers for Immunotherapy: Current Developments and Challenges.

Immunotherapy has revolutionized cancer therapy and has been named the cancer advance of the year for 2016. Checkpoint inhibitors have demonstrated unprecedented rates of durable responses in some of the most difficult-to-treat cancers; however, many treated patients do not respond, and the potential for serious side effects exists. There is a growing need to identify biomarkers that will improve the selection of patients who will best respond to therapy, further elucidate drug mechanisms of action, and help tailor therapy regimens. Biomarkers are being explored at the soluble, cellular, and genomic levels, and examples in immunotherapy include serum proteins, tumor-specific receptor expression patterns, factors in the tumor microenvironment, circulating immune and tumor cells, and host genomic factors. The search for reliable biomarkers is limited by our incomplete understanding of how immunotherapies modify the already complex immune response to cancer, as well as the contribution of immuno-editing to a dynamic and inducible tumor microenvironment and immune milieu. Furthermore, there has been little extension of any candidate assay into large, prospective studies, and the lack of standardization in measurement and interpretation restricts their validity. Both tumor-infiltrating lymphocytes and PD-L1 expression within the tumor microenvironment have been recognized as having both prognostic and predictive value for patients treated with immunotherapy. Alternately, a larger panel of gene signatures, chemokines, and other factors that correlate with response has been proposed. In this article, we will explore the status of current biomarker candidates.

Immune Activation and Benefit From Avelumab in EBV-Positive Gastric Cancer

Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA. Analysis of The Cancer Genome Atlas gastric cancer data (25 EBV+, 80 microsatellite-instable [MSI], 310 microsatellite-stable [MSS]) showed that EBV-positive tumors were MSS. Two-sided Wilcoxon rank-sum tests showed that: 1) EBV-positive tumors had low mutation burden (median = 2.07 vs 3.13 in log10 scale, P < 10-12) but stronger evidence of immune infiltration (median ImmuneScore 2212 vs 1295, P < 10-4; log2 fold-change of CD8A = 1.85, P < 10-6) compared with MSI tumors, and 2) EBV-positive tumors had higher expression of immune checkpoint pathway (PD-1, CTLA-4 pathway) genes in RNA-seq data (log2 fold-changes: PD-1 = 1.85, PD-L1 = 1.93, PD-L2 = 1.50, CTLA-4 = 1.31, CD80 = 0.89, CD86 = 1.31, P < 10-4 each), and higher lymphocytic infiltration by histology (median tumor-infiltrating lymphocyte score = 3 vs 2, P < .001) compared with MSS tumors. These data suggest that EBV-positive low-mutation burden gastric cancers are a subset of MSS gastric cancers that may respond to immune checkpoint therapy.

Oncolytic Viruses—Natural and Genetically Engineered Cancer Immunotherapies

There has long been interest in innovating an approach by which tumor cells can be selectively and specifically targeted and destroyed. The discovery of viruses that lyse tumor cells, termed oncolytic viruses (OVs), has led to a revolution in the treatment of cancer. The potential of OVs to improve the therapeutic ratio is derived from their ability to preferentially infect and replicate in cancer cells while avoiding destruction of normal cells surrounding the tumor. Two main mechanisms exist through which these viruses are reported to improve outcomes: direct lysis of tumor cells and indirect augmentation of host anti-tumor immunity. With these factors in mind, viruses are chosen or modified to selectively target tumor cells, decrease pathogenicity to normal cells, decrease the antiviral immune response (to prevent viral clearance), and increase the antitumor immune response. While only one OV has been approved for the treatment of cancer in the United States, and only two other OVs have been approved worldwide, a wide spectrum of OVs are in various stages of preclinical development and in clinical trials. These viruses are being studied as alternatives and adjuncts to more traditional cancer therapies including surgical resection, chemotherapy, radiation, hormonal therapies, targeted therapies, and other immunotherapies. Here, we review the natural characteristics and genetically engineered modifications that enhance the effectiveness of OVs for the treatment of cancer.

Abstract CT026: Phase 1b study of intratumoral Coxsackievirus A21 (CVA21) and systemicpembrolizumab inadvanced melanoma patients: Interim results of the CAPRA clinical trial

Background: Coxsackievirus A21 (CVA21) is a novel bio-selected oncolytic, immunotherapeutic agent. Intratumoral (i.t.) CVA21 injection can induce selective tumor-cell infection, immune-cell infiltration, IFN-γ response gene up-regulation, increased PD-L1 expression, tumor cell lysis and systemic anti-tumor immune responses. Preclinical studies in an immune-competent mouse model of melanoma have revealed that combinations of i.t. CVA21 and anti-PD-1 blockade mediate significantly greater antitumor activity compared to use of either agent alone. A clinical trial evaluating combination CVA21 and pembrolizumab in patients with melanoma was initiated and preliminary data on a pre-established futility endpoint are presented here. Materials and Methods: This is a single-arm, multi-institutional open-label phase Ib clinical trial of i.t. CVA21 and i.v. pembrolizumab for treated or untreated unresectable Stage IIIC-IVM1c melanoma. Subjects with injectable disease receive up to 3 x 10 8 TCID 50 CVA21 i.t. on Days 1, 3, 5, 8, and then every 3 weeks for up to 19 injections. Subjects also receive pembrolizumab (2mg/kg) i.v. every 3 weeks starting on Day 8. The primary endpoint is safety/tolerability by incidence of dose-limiting toxicity. Secondary endpoints include best ORR by immune-related response criteria, progression-free survival, overall survival, quality of life, changes in melanoma-specific T cells, PD-L1 expression and Th1/Th2 gene expression profiles. The protocol included a futility analysis after the first 12 patients. Results : To date, 14 subjects have started on protocol therapy. Overall, the adverse events have been low-grade constitutional symptoms related to CVA21 and expected pembrolizumab-related side effects. No DLT’s have been reported. Currently, 11 patients are evaluable for investigator response assessment, not including 2 subjects who have not yet reached their first assessment and 1 subject who left the study early due to an unrelated adverse event. Among the evaluable subjects, the ORR was 73% (8/11). The DCR (CR+PR+SD) is currently 91% (10/11). In subjects with stage IVM1c disease, the ORR and the DCR is 100% (5/5). The study has met its primary statistical futility endpoint of achieving ≥2 confirmed objective responses (CR or PR) in the first 12 patients enrolled. Currently, the median time to response is 1.6 months. One of the 8 responders displayed early pseudo-progression and later developed a partial response. Conclusions: At a pre-specified futility analysis, combination CVA21 and pembrolizumab appears to be well-tolerated. Early tumor monitoring has identified encouraging reductions in a number of injected and non-injected lesions. Based on these initial results, the sample size has now been expanded to enroll up to 50 patients. Combination therapy of CVA21 and pembrolizumab may represent a new approach for the treatment of patients with injectable advanced melanoma. Citation Format: Ann W. Silk, Howard Kaufman, Nashat Gabrail, Janice Mehnert, Jennifer Bryan, Jacqueline Norrell, Daniel Medina, Praveen Bommareddy, Darren Shafren, Mark Grose, Andrew Zloza. Phase 1b study of intratumoral Coxsackievirus A21 ( C V A 21) and systemic p emb r olizumab in a dvanced melanoma patients: Interim results of the CAPRA clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT026. doi:10.1158/1538-7445.AM2017-CT026

A phase II trial of riluzole, an antagonist of metabotropic glutamate receptor 1 (GRM1) signaling, in patients with advanced melanoma

Studies demonstrate that GRM, expressed by >60% of human melanomas, may be a therapeutic target. We performed a phase II trial of 100 mg PO bid of riluzole, an inhibitor of GRM1 signaling, in patients with advanced melanoma with the primary endpoint of response rate. Thirteen patients with GRM1‐positive tumors were enrolled. No objective responses were observed, and accrual was stopped. Stable disease was noted in six (46%) patients, with one patient on study for 42 weeks. Riluzole was well tolerated, with fatigue (62%) as the most common adverse event. Downregulation of MAPK and PI3K/AKT was noted in 33% of paired tumor biopsies. Hypothesis‐generating correlative studies suggested that downregulation of angiogenic markers and increased leukocytes at the active edge of tumor correlate with clinical benefit. Pharmacokinetic analysis showed interpatient variability consistent with prior riluzole studies. Future investigations should interrogate mechanisms of biologic activity and advance the development of agents with improved bioavailability.

Interferon Lambda: Toward a Dual Role in Cancer

Interferon (IFN)-λ, a type III interferon (IFN), is a member of a new family of pleotropic cytokines that share high similarity with classical IFNs α and β (IFN-α/β), type I IFNs. IFN-λ acts as an antiviral agent and displays distinct biological functions, including tumor suppression. Although it activates the common Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways, similar to IFN-α/β, IFN-λ differentially induces the expression of IFN-stimulated genes (ISGs). Novel evidence indicates that IFN-λ acts quite differently from IFN-α/β under both homeostasis and pathological situations. In contrast to IFN-α/β, IFN-λ is not involved in over-stimulation of the immune response or exacerbation of inflammation. However, the emergence of unexpected characteristics of IFN-λ, in the control of inflammation and promotion of immune suppression and cancer, reveals novel challenges and offers more strategic opportunities in the context of cancer and beyond. In this article, we discuss new evidence and potential consequences associated with the biology of IFN-λ and provide a different vision for building novel therapeutic strategies in oncology.

Abstract C137: First-in-human dose escalation study of oral ONC201 in advanced solid tumors

Background: ONC201 is an orally active first-in-class small molecule with strong antitumor activity in preclinical models of advanced cancers. In cancer cell lines and patient samples ONC201 induces activation of the integrated stress response (Ishizawa et al ASH, 2014) resulting in upregulation of ATF4 and CHOP which in turn regulates several proapoptotic genes namely DR5. ONC201 also causes late-stage inactivation of Akt and ERK, which also results in downstream activation of the apoptotic TRAIL pathway as part of innate immune surveillance (Allen J et al, Sci Trans Med, 2013). Activity of ONC201 is independent of p53 status and mutation agnostic. ONC201 is well tolerated at efficacious doses in animal models, crosses the blood brain barrier, is particularly effective in refractory tumors, depletes cancer stem cells (Ishizawa et al, ASH 2014; Prabhu et al, Blood 2014; Zhao et al, ASCO 2014), and is effective with infrequent dosing preclinically. Based on the compelling efficacy and safety profile of ONC201 as well as the engagement of signaling pathways critical for many cancers, the clinical introduction ONC201 in advanced cancer patients is warranted. Methods: The first-in-human study of ONC201 (NCT02250781) began in January 2015 as an open-label single-site phase I trial enrolling adult patients with refractory advanced solid tumors and glioblastoma (GBM). Patients with symptomatic brain metastases or prior bevacizumab for treatment of GBM are excluded. The primary endpoint is determination of the recommended phase II dose (RP2D) of single agent ONC201 given orally once every 3 weeks (1 cycle). Secondary endpoints include assessment of pharmacodynamics using select biomarkers for ONC201 (Allen et al, 2015), pharmacokinetics, toxicity, and efficacy. The study employs an accelerated, single patient per cohort, dose escalation design with expansion to a standard 3+3 design if a subject has grade > / = grade 2 toxicity or dose limiting toxicity within cycle 1. The maximum tolerated dose is the highest dose level in which 6 patients have been treated with Results: Single patient dose escalation was completed in cohorts 1 to 4 and 6 patients completed at least 3 weeks of level 5 without any > / = grade 2 drug related toxicity. At DL 6, Mean T1/2 = 7.91hours (7.01-9.42); Mean Cmax = 8.58 ug/mL (3.95 - 19.15) Mean AUC(0-24) = 28057 (15293 - 50597) hr-ng/mL. Ongoing radiographic stable disease is noted in a patient with metastatic castrate resistant prostate cancer. Conclusions: The RP2D of ONC201 is 625mg on a once every 3 week schedule. Evaluation of PD markers of response and enrollment to a dose expansion safety cohort are ongoing. Citation Format: Mark N. Stein, Rebecca Moss, Tina Mayer, Ann W. Silk, Nancy Chan, Ling Zheng, Yasmeen Beckett, Noelle Tenpenny, Edward Bentlyewski, Robert DiPaola, Rohinton Tarapore, Joshua Allen, Janice Mehnert. First-in-human dose escalation study of oral ONC201 in advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C137.

Efficacy and safety of high-dose interleukin-2 treatment in patients with a history of brain metastases from renal cell carcinoma

Meeting abstracts The efficacy and safety of high dose IL-2 therapy in patients with brain metastases due to renal cell carcinoma is not well characterized. Data were prospectively collected in a registry of 371 patients with RCC receiving high-dose IL-2, including 18 patients with a history of