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Unmet medical need in solid tumor immunotherapy Filip Janku, MD, PhDAssociate ProfessorClinical & Translational Research Center Medical Director Investigational Cancer Therapeutics(Phase I Clinical Trials Program)MD Anderson Cancer CenterHouston, TX
Response rates to checkpoint inhibitors in approved indications Melanoma Pembrolizumab: RR ~ 30% Nivolumab/ipilimumab: RR ~ 50%Non-small lung cancer Pembrolizumab: RR ~ 20%-40%Nivolumab: RR ~ 20%SCC of head and neck Pembrolizumab: RR ~ 18%Nivolumab: RR ~ 13% Urothelial cancer Pembrolizumab: RR ~ 21%Nivolumab: RR ~ 28%Atezolizumab: RR ~ 15%-26% Robert NEJM 2015Wolchok NEJM 2013Garon NEJM 2015Reck NEJM 2016Ferris NEJM 2016Chow J Clin Oncol 2016Bellmunt 2017Rosenberg 2016
Classification by tumor immune phenotype in urothelial cancers Immune excluded (CD8 trichrome stain) Mariathasan S. Nature 2018
Immunotherapy: unmet need MSI-H: ~5% of mCRC Siegel CA J Cancer Clin 2018 Ovarian cancerSoft tissue sarcomasGliomaMyeloma
Predictive factors for response to immune checkpoint inhibitors PD-L1 expression TMB MSI-H/dMMR
Stimulatory and Inhibitory Factors in the Cancer-Immunity Cycle Chen DS. Immunity 2013
Mechanisms of immunoresistance Syn Lancet Oncol 2017Blank Science 2016
Converting Cold Tumors into Hot Haanen Cell 2017
Patient with MPNST (sarcoma) with spontaneous remission after prolonged infection with coagulase negative staphylococcus and Klebsiella Pneumoniae January 2013 May 2013 September 2013 Prolonged infection with bacteremia January to February 2013
Anticancer activity of single intratumor injection of Clostridium Novyi-NT Janku CRI-CMIT-EATI-AACR 2018
Cytokine response after single intratumor injection of Clostridium Novyi-NT Janku CRI-CMIT-EATI-AACR 2018
Antitumor Activity of STING Barber Nat Rev Immunol 2015
Harrington ESMO 2018 Phase I: Intratumor STING agonist MK-1454 +/- pembrolizumab Phase I: Accelerated Titration Design -> modified Toxicity Probability IntervalEndpointsPrimary: safety, doseSecondary: PK/PDExploratory: objective responseDLTs:Monotherapy (26 patients): G3 vomiting (1)Combination (25 patients): G2 erythema multiforme (1), G3 injection site pain (1), G3 skin/tumor necrosis (1) AEs: Pyrexia (65.2%/42.9%), chills (39.1%/25%), injection site pain (47.8%/10.7%), fatigue (34.8/25%)
Harrington ESMO 2018 Phase I: Intratumor STING agonist MK-1454 +/- pembrolizumab EFFICACYMonotherapyMyoepitehlial carcinoma > - 30% (not confirmed as PR)2 patients with shrinkage of injected lesionsCombinationPartial response: 6 (TNBC, 1; HNSCC, 3; ATC, 2)Shrinkage of injected and noninjected lesions observed PRs were durable (>6 months)Median 83% reduction in size of target lesions for responders
SITC 2018: MIW815 STING agonist 41 pretreated patients with solid tumors or lymphomasNo DLTsThe most common AEs: pyrexia (7; 17.1%), injection site pain (6; 14.6%), headache (6; 14.6%). Grade 3/ 4 AEs: increased lipase (2; 4.9%), elevatedamylase, tumor pain, dyspnea, respiratory failure,and injection site reaction (1 each; 2.4%). On-treatment tumor biopsies showed increases in CD8 T cells infiltrating the injected tumors in a subset of patients. PR: Merkel cell (CPI na ve), Parotid gland (CPI pretreated), both response appear to be durable Meric-Bernstam. SITC 2018
STING agonists in the clinic MK-1454: early data for monotherapy and combination with pembrolizumab presented at ESMO 2018MIW815: early data for monotherapy presented at SITC 2018MK-2118: clinical trial ongoing (monotherapy and combination with pembrolizumab)
Conclusions Immunotherapy with immune checkpoint inhibitors can be effective in subsets of patients with melanoma, lung cancer and other tumor typesImmunotherapy with immune checkpoint inhibitors has not shown enough activity resulting in FDA approval in many common cancers including breast cancer, prostate cancer, ovarian cancer, MSS colorectal cancer and sarcomas, which creates unmet need for novel therapeutic approachesTurning cold tumors into hot with activators of innate immunity such as STING agonists (and others) offers a new promising approach to increase efficacy of cancer immunotherapy
Role of type I IFN in tumor immune recognition and therapy Dmitriy Zamarin MD PhDAssistant Attending PhysicianTranslational Research DirectorGynecologic Medical Oncology ServiceImmunotherapeutics ServiceMemorial Sloan Kettering Cancer Center
Type I IFN: the first cytokine Alick Isaacs Jean Lindenmann Isaacs, A., and Lindenmann, J., Proc. Roy. Soc., B, 147, 258 (1957)
Functions of type I IFN in infection Ivashkiv et al. Nat Rev Immunol 2013
Cross-talk between type I IFN and adaptive immunity Trinchieri G, JEM 2010.
Type I IFN- related transcripts correlate with T cell infiltration in tumors Fuertes M.B. et al., JEM. 208:2005-16 (2011)
Type I IFN signature is associated with clinical benefit from ipilimumab in melanoma Chiappinelli et al., Cell 2015
Type I IFN pathway is essential for the efficacy of cancer immunotherapy a. Zamarin D, Wolchok JD, Allison JP. Sci Transl Med. 2014 5:226ra
Mechanisms of activation of type I IFN pathway
STING pathway is required for immune recognition and elimination of tumors. Woo . Gajewski. Immunity 2015.
Therapeutic strategies to target type I IFN pathway in cancer TLR agonistsSTING agonistsVirusesBacteriaEngineered viruses and bacteria