IL-10 is anti-inflammatory and stimulates the cytotoxicity and proliferation of CD8+ T cells at higher concentrations. IL-10 receptors and PD1 are expressed on activated and exhausted CD8 T cells, providing a rationale for combining AM0010 and an anti-PD1 antibody. 4 of 16 heavily pre-treated pts with poor- or intermediate-risk mRCC, achieved a PR with AM0010 alone.
38 pts with metastatic RCC were enrolled from 2/20/2015 to 11/18/16 on AM0010 (10 or 20 ug/kg daily SC) and nivolumab (n = 29; 3mg/kg, q2wk IV) or pembrolizumab (n = 9; 2mg/kg, q3wk IV). Three had favorable and 30 had intermediate or poor-risk by IMDC (5 data not available). Pts had a median of 1 prior therapy (range: 1-3), and at least one VEGFR-TKI. One patient with prior AM0010 was included the safety population only. Tumor responses were assessed by irRC. Serum cytokines, blood derived T cells, clonal identity of peripheral T cells, and tumor DNA sequence and mRNA profiling were assayed.
AMO010 plus nivolumab (nivo) or pembrolizumab (pembro) was well tolerated. TrAEs were reversible and transient. G3/4 TrAE in patients on AM0010 and nivo or pembro included anemia (10), thrombocytopenia (7), and hypertriglyceridemia (6). Two pts had a reversible cytokine release syndrome with splenomegaly and increased immune mediated red blood cell phagocytosis (HLH) most likely precipitated by T-cell activation, as both pts had a PRs. Patients treated with 10ug/kg AM0010 and nivo or pembro did not have G3/4 anemia or thrombocytopenia. As of August 11 2017, PRs were observed in 14 of 34 evaluable pts (41%). An additional 13 pts had stable disease (38%), 8 of those had a tumor reduction of more than 30% following irRC (in progress). Median PFS and median OS have not been reached, at median FU of 13.5 months (range: 0.5-29.83) for the nivolumab arm. mRNA analysis was used to distinguish patients with CR/PR/SD from progressive disease. Responding patients had a higher degree of CD8+ T cell invigoration.
The combination of AM0010 with nivo or pembro is well-tolerated in mRCC pts; the recommended phase 2 dose is 10ug/kg. The observed efficacy is very promising and further studies of AM0010 and nivo or pembro in mRCC are in preparation.
NCT02009449
ARMO BioSciences
ARMO BioSciences
A. Hung, P. Van Vlasselaer: Employee of ARMO BioSciences. M. Oft: Founder and employee of ARMO BioSciences. All other authors have declared no conflicts of interest.
E7046 is a selective small molecule antagonist of the prostaglandin E2 receptor-type-4 that inhibits the differentiation of monocytic myeloid lineage cells towards a pro-tumorigenic phenotype in the TME. This is a first-in-human study of single agent E7046.
Key eligibility criteria: patients (pts) ≥18 years with selected advanced cancers with high levels of myeloid infiltrate. The dose-escalation phase consisted of 6-pt cohorts of 125, 250, 500, and 750 mg (once-daily, oral, 21-day cycle) doses of E7046. Primary objectives were safety/tolerability, maximum tolerated dose (MTD) and/or RP2D. Secondary objectives included PK and initial anti-tumor activity; exploratory objectives included PD assessments on immune cells in tumor infiltrate and in peripheral blood and metabolic response by 18FDG-PET.
30 pts received E7046 (median age 58 yrs [24-78]; 2-7 lines of prior therapy). Most common tumor types were colorectal cancer (40%), pancreatic cancer (20%), and SCCHN (13%). No DLTs were observed and the MTD was not reached. The most frequent drug-related adverse events (AEs) were diarrhea (20%), decreased appetite, fatigue and nausea (13% each). Drug-related AEs of Gr 3/4 occurred in 4 pts (diarrhea, anaphylactic reaction, hypersensitivity, hyperuricemia, rash, generalized rash). 2 pts had drug-related serious AEs (rash, allergic reaction, fever in 1 pt; hyperuricemia, acute renal failure [Gr 2] in 1 pt). 3 pts discontinued treatment due to AEs (bowel obstruction, allergic reaction, abdominal pain). There were no drug-related deaths. E7046 exposure was dose proportional up to 500 mg with no incremental increase in exposure at 750 mg. E7046 was extensively metabolized, elimination half-life was ∼12hr and accumulation on multiple dosing was ∼2-fold. 2 pts are ongoing and preliminary efficacy showed no objective responses, 4 pts with durable SD or clinically stable (>4 mo) and 4 pts with 18FDG-PET metabolic responses.
Single-agent E7046 was tolerated with no MTD reached in heavily pretreated pts with myeloid-rich tumors. PD analysis of immune cell modulation to help determine the RP2D will be presented at the meeting.
NCT02540291
Eisai Inc.
Eisai Inc.
D. Hong: Research/Grant Funding: Bayer, Lilly, Genentech, LOXO, Pfizer, Amgen, Mirati, Ignyta, Merck, Daichi-Sanko, Eisai; Travel, accommodations, expenses: MiRNA, LOXO; Consulting or Advisory Role: Bayer, Baxter, Guidepoint Global; Other ownership interests: Oncoreseponse (founder). A. Parikh: Personal fees from Roche, outside the submitted work. G. Shapiro: Consulting: Pfizer, Lilly, G1 Therapeutics, Vertex, Roche; Research funding: Lilly. L. Reyderman, M. Ren, T. Binder, C.E. Ooi: Employee of Eisai Inc. S. Dayal: Employee of Eisai Ltd. Ö. Ataman: Former employee of Eisai Ltd. at time of study. A. Marabelle: Received clinical trial funding from Eisai; Received consulting fees from Eisai and Roche; Received funding for anti-CSF1R clinical trial from Roche. All other authors have declared no conflicts of interest.
Omaveloxolone (Omav) reduces production of reactive oxygen and nitrogen species by myeloid derived suppressor cells (MDSCs) and restores immune surveillance in preclinical cancer models. Administration of Omav with checkpoint inhibitors (CI) may enhance the anti-tumor immune response of immunotherapies. A Phase 1b/2 study was designed to evaluate the safety and efficacy of Omav in combination with ipilimumab (Ipi) or nivolumab (Nivo) for treatment of patients with unresectable or metastatic melanoma. Data from the ongoing Phase 1b study are reported.
Patients with or without prior exposure to CI, and with >5% of tumor cells from a screening biopsy positive for inducible nitric oxide synthase (iNOS) were enrolled. Serial biopsies were also collected at Weeks 2 and 13. Omav monotherapy (5, 10, 20, 100, or 150 mg PO QD) was dosed continuously starting one week prior to CI initiation (Ipi x 4 doses or Nivo q 2 weeks). Primary objectives were safety, MTD, and ORR measured via RECIST v1.1.
At data cutoff, 39 patients were enrolled (Omav + Ipi: n=12; Omav + Nivo: n=27) with median treatment duration of 13 weeks. Of 30 patients with evaluable tumor restaging, 7/30 (23%) of patients were CI-naïve, while 23/30 (77%) of patients were refractory to prior CI therapy. The ORR (confirmed + unconfirmed) observed in all evaluable patients was 8/30 (27%, 6 partial response (PR) and 2 complete response (CR)) and 4/7 (57%) in CI-naïve patients, including 1 CR. 3/18 (17%) patients treated with Omav + Nivo who were refractory to prior CI therapies had objective responses including 1 CR. Omav was associated with decreases in tumor iNOS, PD-L1, and IDO-1 expression. The MTD for Omav has not been established since no dose-limiting toxicities were observed. No serious AEs considered related to Omav have been reported to date. Commonly reported treatment-related adverse events included fatigue, nausea, pruritus, transaminase increases and decreased appetite.
Omav was well tolerated at doses up to 150 mg in combination with CI and initial efficacy data suggest that Omav may overcome CI resistance. The Phase 2 portion of the trial will study the effects of Omav with Nivo in patients refractory to prior anti-PD-1/PD-L1 therapies.
NCT02259231
The genome of cancer cells is inherently instable promoting multiple genomic alterations and epigenetic changes. This process leads to a unique molecular profile of every given tumor. Recently, a series of independent reports revealed that neo-antigen specific T-cell responses are seminal for the clinical efficacy of immune checkpoint inhibitors. However, less than 1% of mutations appear to raise spontaneously occurring T-cell response in the tumor-bearing patient. Accordingly, only patients with a high burden of mutations profit from currently approved therapies. To overcome this restriction, the IVAC® MUTANOME, a highly potent personalized neo-antigen-encoding RNA vaccine approach, harnesses the individual patient’s mutation profile. To this aim, the individual mutation repertoire is identified by next-generation-sequencing and 10 potentially immunogenic mutated sequences per patient are selected. These are incorporated into a poly-epitopic RNA vaccine (IVAC MUTANOME®) that is tailored to activate and expand the individual patient’s T cells against the unique mutation signature.
A phase I first-in-human trial has been initiated in 2013 in patients with stage III and IV malignant melanoma (NCT02035956) to test this fully personalized RNA vaccine concept. The objective of this clinical trial is to study the feasibility, safety, tolerability, immunogenicity and the potential anti-tumoral activity of the IVAC® MUTANOME approach.
As of November 2016, 13 patients were evaluable for the assessment of the safety profile and the induction of antigen-specific immune responses. Notably, in each and every patient a strong poly-neo-epitopic immune response against vaccine antigens was detected. Overall, 60% of the 125 selected neo-epitopes elicited a T-cell response. Simultaneously, no severe adverse drug reactions were reported and indications for clinical activity were observed.
Vaccination with IVAC® MUTANOME was very well tolerated. A high pharmacological activity of the vaccine was observed in all enrolled patients encouraging further clinical development.
NCT02035956; First Posted: January 14, 2014
Biontech RNA Pharmaceuticals GmbH
CI3 cluster program of the German Federal Ministry of Education and Research (BMBF).
M. Miller, K. Schreeb, S. Bolte: Employee of BioNTech AG. U. Sahin: Stock owner and management board member of BioNTech group; Co-founder and CEO BioNTech AG, Mainz. Head of the Scientific Advisory Board of Ganymed Pharmaceuticals AG. E. Derhovanessian, B-P. Kloke, P. Simon, V. Bukur, C. Albrecht, A. Kuhn, A. Kemmer Brueck, A. Paruzynski: Employee of the BioNTech group. S. Grabbe: AbbVie: Advisory Board, Reimbursement of travel costs. BMS: Advisory Board, Honorarium (oral presentation), Reimbursement of travel costs. MSD: Advisory Board, Honorarium (oral presentation), Reimbursement of travel costs. OnkoZert: Honorarium (Auditor), Reimbursement of travel costs. Roche: Advisory Board, Honorarium (oral presentation), Reimbursement of travel costs. Sanofi-Pasteur-MSD: Advisory Board, Reimbursement of travel costs. Takeda: Reimbursement of travel costs. Novartis: Advisory Board, Reimbursement of travel costs. MedConcept: Honorarium (oral presentation), Reimbursement of travel costs. Beiersdorf: Honorarium (oral presentation), Reimbursement of travel costs. L'Oreal: Honorarium (oral presentation), Reimbursement of travel costs. Merck Sero: Advisory Board, Reimbursement of travel costs. C. Höller: Speaker for Amgen, BMS, MSD, Novartis, Roche; Advisor for Amgen, BMS, Incyte, MSD, Novartis, Pierre Fabre, Roche. Ö. Türeci: Co-founder of Ganymed Pharmaceuticals AG. Member of Scientific Advisory Board of BioNTech AG. J. Utikal: Member of advisory boards and on speakers’ bureaus: Amgen, BMS, GSK, MSD, Novartis, Roche. C. Huber: Co-founder, shareholder, advisor und deputy chairman supervisory board BioNTech. C. Loquai: Advisory board: Roche, Novartis, Pierre Fabre, MSD, BMS, Leo, Amgen, Biontech; Speekers fee: Roche, Novartis, Pierre Fabre, MSD, BMS, Amgen; Travel Reimbursement: Roche, Novartis, MSD, BMS, Amgen. All other authors have declared no conflicts of interest.
Our group has previously demonstrated the importance of the clonality of cancer mutations in predicting overall survival in NSCLC and response to checkpoint blockade. Genomic analysis of the first 100 cases within the lung TRACERx study has shown an increased risk of recurrence or death associated with increased intratumoural heterogeneity. Conceivably, the level of mutational burden and genomic heterogeneity could be reflected in the adaptive anti-tumoural immune response in these patients.
Here, we report TCR sequencing data from multi-region tumour specimens and normal lung in patients within the lung TRACERx study with either genetically heterogeneous (high ITH) or homogenous (low ITH) NSCLC tumours.
We found that the TCR repertoire in tumour specimens is distinct to that observed in normal lung with the majority of CDR3 sequences found to be unique to either compartment, suggestive of a repertoire of T cells spatially confined to the tumour microenvironment, possibly driven by the presence of tumour antigen. We observed a significantly lower degree of overlap in the TCR repertoire between matched normal tissue and tumour tissue compared to the TCR repertoire across multi-region tumour specimens. TCR repertoire heterogeneity was found to reflect neoantigen heterogeneity; we found a significantly higher degree of TCR repertoire overlap, as assessed by the Jaccard index of the 100 most abundant TCRs, in patients with low ITH tumours as compared to high ITH tumours. Moreover, we observed a correlation between TCR clonality and neoantigen load in patients with low ITH tumours.
Taken together, these findings demonstrate a heterogeneous spatial distribution of tumour infiltrating lymphocytes among patients with NSCLC. Theoretically TCR clones, present across multiple regions of the tumour may expand in response to common neoantigens found in all cancer cells and efforts are currently underway to determine the antigen specificity of such TCRs. The observations described are indicative of a dynamic intra-tumoural T cell response that may be accounted for by differences in the genetic heterogeneity in the mutational and predicted neoantigen burden observed in NSCLC.
None
K. Peggs, S. Quezada: Founder of Achilles Therapeutics. C. Swanton: Receipt of grants/research supports: Pfizer; Receipt of honoraria or consultation fees: Roche Ventana, Celgene, Pfizer, Novartis; Stock shareholder: Grail, Epic Biosciences, Apogen Biotechnologies, Achilles Therapeutics. All other authors have declared no conflicts of interest.