Immunotherapy for Glioblastoma: Updates and Future Directions Stephen Bagley, MD, MSCE Instructor of Medicine Friday, June 8, 2018 Disclosures I have research funding support from Incyte, Novocure, Eli Lilly, and Tesaro. I have no financial conflicts of interest related to this presentation. Please note that some of the studies reported in this presentation were published as an abstract and/or presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal. 2 Overview 1) Brief background: cancer immunotherapy 2) Recent key immunotherapy studies in glioblastoma 3) Specific challenges in glioblastoma immunotherapy 3 4 FDA approvals for immune checkpoint inhibitors (as of 3/23/18) 5 Ribas, et al Science 2018 Chimeric antigen receptor (CAR) T cells for hematologic malignancies • CAR T cells FDA approved for: • Refractory pre-B cell acute lymphoblastic leukemia • Refractory diffuse large B cell lymphoma 6 Cancer evasion of immunosurveillance Glioblastoma 7 Vonderheide, Cancer Cell 2018 Classes of Cancer Immunotherapy • Systemic cytokine therapy • Interferons • Interleukins • Vaccines • Peptide • Dendritic cell • DNA • Monoclonal antibodies • Immune checkpoint inhibitors • Co-stimulatory receptor agonists • Small molecules • IDO inhibitors, many others • Oncolytic viral therapy and immunotoxins • Adoptive T cell Transfer 8 Vonderheide, Cancer Cell 2018 Local and systemic immunosuppression in glioblastoma 9 Lim et al, Nat Rev Clin Oncol 2018 Overview 1) Brief background: cancer immunotherapy 2) Recent key immunotherapy studies in glioblastoma 3) Specific challenges in glioblastoma immunotherapy 10 Classes of Cancer Immunotherapy • Systemic cytokine therapy • Interferons • Interferon-beta treatment has been shown to • Interleukins yield a net immune stimulating effect against • Vaccines glioblastoma initiating cells (stem cells) • Peptide • In older clinical trials, only limited clinical activity • Dendritic cell of interferon-beta and interferon-alpha therapies in combination with alkylating • DNA chemotherapy for high grade glioma • Monoclonal antibodies • Phase III trial ongoing in China • Immune checkpoint inhibitors • Interferon-gamma is currently being studied in • Co-stimulatory receptor agonists combination with DNX-2401 (oncolytic • Small molecules adenovirus) for recurrent glioma • IFN-gamma very poorly tolerated, did not seem to • IDO inhibitors, many others improve outcomes compared to DNX-2401 alone • Oncolytic viral therapy and (Lang et al, SNO 2017) immunotoxins • IL-12 and GM-CSF used as vaccine adjuvants • Adoptive T cell Transfer Wolpert et al,, PLoS One 2015; Yamamuro et al, Int J Oncol 2015 11 Buckner et al, Cancer 2001; Groves, et al, Br J Cancer 2009 Motomura et al, Cancer 2011 Classes of Cancer Immunotherapy • Systemic cytokine therapy • Interferons • Interleukins • Vaccines • Peptide • Dendritic cell • DNA • Monoclonal antibodies • Immune checkpoint inhibitors • Co-stimulatory receptor agonists • Small molecules • IDO inhibitors, many others • Oncolytic viral therapy and immunotoxins • Adoptive T cell Transfer 12 Vaccine Therapies for Glioblastoma • Previously considered one of the most promising approaches to improving the outcomes of patients with glioblastoma “Cold” “Hot” • Negative results from several phase II and phase III trials have challenged the concept of vaccination as a single-modality immunotherapy 13 Johnson et al, Clin Cancer Res 2017 Rindopepimut (CDX-110, PEPvIII) • Peptide vaccine that mimics EGFR ACT IV Trial: Randomized, Phase III trial variant III (EGFRvIII), a in newly diagnosed EGFRvIII+ GBM constitutively active mutant form of EGFR expressed exclusively on • N=745, GBM s/p maximal surgical resection and GBM cells in 25–30% of patients standard chemoradiation • Advantage: neoantigen expressed without progression • 405 patients with MRD exclusively on tumor cells, limiting (<2cm2 contrast enhancing risk of “on-target, off-tumor” tumor) toxicities • 1:1 randomization to rindopepimut vs. control via • Disadvantage: EGFRvIII is monthly intradermal injection heterogeneously expressed (both concurrent with TMZ spatially and temporally) on GBM • Primary endpoint: OS in the MRD subgroup cells in vivo 14 Del Vecchio et al, Oncogene 2013 Weller et al, Lancet Oncol 2017 Rindopepimut: Issues and Future Directions • Is a certain level of tumor tissue needed to drive immune responses? • RT and TMZ-induced lymphopenia • Spontaneous loss of antigen expression, even in the control arm, as observed in patients undergoing repeat surgery • Failure of a strong humoral immune response to translate into clinical benefit • Are vaccines the right approach in GBM? *** Non-comparative phase II trial (ReACT): • Bevacizumab-naïve recurrent GBM patients (n=72) with EGFRvIII+ tumors randomized to bevacizumab plus double-blinded injection of rindopepimut or control (KLH) • PFS-6 of 27% versus 11% (p=0.048) • Median OS 12.0 vs. 8.8 months (p=0.02) Weller et al, Lancet Oncol 2017 15 Reardon et al, ASCO 2015 ICT-107: a multipeptide dendritic cell vaccine • Patient-derived dendritic cells Randomized, Phase II Trial (post-surgery apheresis) • N=124, newly diagnosed GBM incubated ex vivo with six • <1cm3 residual tumor, completed first-line peptides commonly over- chemoradiation •Phase77 patients III (62%) trial HLA was-A2 positive opened for expressed in GBM cells compared • Randomized 2:1 to ICT-107 or control to nonmalignant tissues patient(autologous DCsaccrual not exposed in to 2016 the GBM but (“warehouse” approach using antigens) • wasinduction terminated QWx4 vaccinations, due followed to lackby tumor-associated antigens): ofmaintenance funding vaccinations on June plus TMZ 21, 2017 • Melanoma-associated antigen 1 (MAGEA1) • Median PFS improved with ICT-107 (HR 0.57, p=0.01). • HER2 • interferon-inducible AIM2 Median OS favored ICT-107 by 1.6 months in ITT • I-dopachrome tautomerase (DCT) group (NOT statistically significant; p=0.64) • melanocyte protein (PMEL) • HLA-A2+ subgroup: median OS 18.3 months with • IL-13 receptor subunit-alpha2 (IL- ICT-107 v. 12.9 months with control 13Ralpha2) 16 Phuphanich, et al, Cancer Immunol. Immunother 2013 Wen et al, SNO Annual Meeting 2014 DCVax-L (Northwest Biotherapeutics): whole tumor lysate used to pulse autologous dendritic cells • Serves as a source for the • Two prior phase I/II studies at UCLA entire spectrum of tumor • N=20 newly diagnosed GBM antigens (“personalized” • Median PFS ~24 months • Median OS ~36 months (with reported “tail” of vaccine), but logistically survivalStill curve) no published data challenging (requires • As of July, 2011, 33% of patients had reached or (orexceeded anything 4 years’ median peer OS and reviewed 27% had reached collection of tumor sample or exceeded 6 years median OS from each individual • Most forrecently presentation the company reported two at patients a have patients for processing and exceeded 10 years’ survival • Phase III scientifictrial ongoing (started meeting) 12/2006): DC stimulation) most patients on control arm crossed over to DCVax • 25 patients treated in an Information Arm (“indeterminate progressors”) after vaccine was already produced: • median OS 21.5 months, with 24% of patients Liau et al, Clin Cancer Res 2005 exceeding 48 month OS 17 https://www.nwbio.com/dcvax-l/ Other Vaccines: ongoing trials and future directions • IDH peptide vaccines • 2 phase I trials ongoing (NOA-16 and RESIST): IDH1-R132H-mutated peptide vaccines • HSPPC-96 (antigenic tumor peptides bound to HPS-96) • Phase I, multicenter phase II trials of HSPPC-96 reported in recurrent GBM; 90% of patients with OS > 6 months. • However, randomized PhII trial of HSPPC-96 with bev vs. bev alone was negative (Bloch et al, SNO Annual Meeting 2017) • DNA vaccines: • VXM01: VEGFR2 expression plasmid encoded in live, attenuated Salmonella bacteria (NCT02718443) • INO-5401: WT1, hTERT, and PSMA (given via IM electroporation) (NCT03491683) • Viral Antigens: • High percentage of CMV gene products expressed in malignant gliomas (but not surrounding brain tissue) • Pp65: dominant CMV epitope expressed in 50-70% of newly diagnosed GBM: • Phase I study: 6 patients treated with DCs pulsed with CMV pp65 RNA (preconditioned the vaccine site with tetanus/diphtheria (Td) toxoid): • 50% OS rate at 40 months • Use of adjuvants aimed at stimulating myeloid compartment • SL-701, e.g.: an emulsion of multivalent glioma-associated antigens (short synthetic peptides, including IL13R, survivin, others) administered with poly-ICLC adjuvant • Preliminary phase II data presented at SNO 2017 Annual Meeting • Partial and complete responses demonstrated, tail to survival curve Rampling R, Clin Cancer Res 2016 Bloch et al, Neuro Oncol 2014 18 Mitchell et al, Nature 2015 Reardon, Neuro Oncol 2017 Classes of Cancer Immunotherapy • Systemic cytokine therapy • Interferons • Interleukins • Vaccines • Peptide • Dendritic cell • DNA • Monoclonal antibodies • Immune checkpoint inhibitors • Co-stimulatory receptor agonists • Small molecules • IDO inhibitors, many others • Oncolytic viral therapy and immunotoxins • Adoptive T cell Transfer 19 Immune checkpoint inhibition… Must be preceded by… T cell priming Salama et al, Clin Cancer Res 2011 20 FDA approvals for immune checkpoint inhibitors (as of 3/23/18) 21 Ribas, et al Science 2018 Neoantigens increase likelihood of T cell priming against the tumor 22 Mutational burden and benefit from immune checkpoint inhibition Melanoma NSCLC Johnson et al, Cancer Immunol Res 2016