Cancer immunotherapy with oncolytic viruses: more than just lysis

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1 Cancer immunotherapy with oncolytic viruses: more than just lysis Dmitriy Zamarin MD PhD Assistant Attending, Immune Therapeutics Center Memorial Sloan-Kettering Cancer Center New York, NY BCAN Think Tank 2016 August 13, 2016

2 PD-L1 blockade with atezolizumab in patients with advanced bladder cancer Unrestrained Activation/Proliferation Anti-PD-1 T cell Anti- PD-L1 Anti- CTLA-4 APC Immune checkpoint blockade Rosenberg JE, et. al, Lancet 2016

3 Immune-active microenvironment in human cancers is associated with clinical benefit from immunotherapies CD8 How? No benefit Benefit Type I IFN signature is associated with clinical benefit from CTLA-4 blockade in melanoma Chiappinelli et al., Cell 2015 Positive correlation between increased T cell infiltration and type I IFN-induced transcripts Fuertes M.B. et al., JEM. 208: (2011)

4 Newcastle Disease Virus () F HN M Negative-strand RNA virus, member of Paramyxoviridae family (same as mumps, HPIV, measles), which do not integrate into genome N L P Causes contagious bird disease affecting many domestic and wild avian species, but poses no hazard to human health Specificity for cancer cells is mediated by selective viral replication in cells with deficient innate immune responses and cells resistant to apoptosis Readily infects the majority of cancer cells due to ubiquity of the receptor (sialic acid) Strong inducer of type I interferon and dendritic cell maturation

5 Clinical trials with systemicallyadministered naturally-occurring Type of cancer Type of study and patient number (n) Various advanced Phase I, n=79 Various advanced Phase I, n=16 Various advanced Phase I, n=18 Clinical outcome 1 Zamarin D and Palese P. Future Microbiol Mar;7(3): CR (H&N), 1 PR (CRC), 14 SD Improved tolerability with desensitization 1 CR (cervical), 5 PR (CRC, carcinoid, melanoma), 5 SD (CRC, ovarian) Ref. (Lorence, Roberts et al. 2007) (Laurie, Bell et al. 2006) (Hotte, Lorence et al. 2007) Hotte et al., Clin Canc Res. Future Microbiol :977

6 is effective in orthotopic xenograft models of human cancers Malignant Pleural Mesothelioma Peritoneal Gastric Cancer Control Control Day 1 Day 3 Day 7 Day 13 Day 22 Day 3 Day 7 Day 13 Day 22 Day 103 Mol Cancer Ther Oct;9(10): J Mol Med (Berl) June; 88(6):

7 Nonpathogenic infects and lyses bladder cancer cell lines Absorbance at 570nm *** * **** **** **** **** **** *** ** **** **** **** **** KU19-19 MGHU3 MGHU4 T24 235J 575A 639V UM4C6 TCC-Sup J82 SW1710 YMCUB MTT proliferation assay, 48 hours post-infection PBS

8 Immunogenic cell death and inflammation induced by oncolytic viruses HSPs Ecto-CRT Activation and recruitment of innate and adaptive immune effectors B7-1,2 1. MHC, 2. Costimulatory ligands MHC 3. Surface HSPs and ecto-calreticulin 4. Type I IFN PAMPS virus 1.TAA s, 2.DAMPS PAMPS 1. DC maturation 2. MHC 3. Costimulatory ligands 4. Cytokines, chemokines

9 MHC I MFI induces immunogenic cell death in bladder cancer cells Calreticulin MFI Surface MHC I *** **** **** **** **** * ns **** **** * **** ns ns KU19-19 MGHU3 MGHU4 T24 235J 575A 639V 5637 J82 SW1710 TCC-SUP UM4C6 YMCUB2 PBS KU19-19 MGHU3 Surface calreticulin **** **** **** **** **** ns ns **** **** **** **** *** **** MGHU4 T24 235J 575A 639V 5637 J82 SW1710 TCC-SUP UM4C6 YMCUB2 PBS

10 Cells /g tumor Intratumoral treatment results in immune recognition of both virus-injected and distant tumors B16-F10 melanoma MB49 bladder carcinoma Distant tumor Virus-treated tumor mock B16 melanoma ** * **** ns h 48h 72h 96h mock mock 0 CD3+ CD8+ CD4+FoxP3- CD4+FoxP3+ MB49 bladder mock Zamarin D, Wolchok JD, Allison JP. Science Translational Medicine :226ra

11 Cells /g tumor therapy induces tumor infiltration with antigen-specific cells B16-B16 B16-MC38 Pmel (CD8) CD8+Thy *** **** PBS right B16 right B16 PBS right MC38 right MC38

12 Percent survival Percent survival potentiates the efficacy of CTLA-4 blockade against virus-treated and distant tumors No response to CPI PBS Response to CPI MB49 p= Days p= PBS actla-4 +actla B16-F10 80 Response to CPI? *** Days post challenge * PBS +isotype PBS+anti-CTLA-4 +anti-ctla-4

13 Intratumoral T-VEC in combination with ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma Puzanov I, et al., JCO 2016

14 infection upregulates expression of PD-L1 on tumor cells and infiltrating leukocytes PD-L1 MFI 5000 *** **** **** **** **** **** **** *** **** ns **** ** *** KU19-19 MGHU3 MGHU4 T24 235J 575A 639V 5637 J82 SW1710 TCC-SUP UM4C6 YMCUB2 PBS CD11b PD-L1

15 PD-L1 expression in bladder cancer Powles T., et al. Nature 2014

16 Percent survival Combination therapy with and immune checkpoint blockade reject virus-injected and distant B16 melanoma and MB49 bladder carcinoma tumors **** *** ** *** Percent survival B16-F10 melanoma Survival Days PBS+Ig +Ig PBS+anti-PD-1 +anti-pd-1 PBS+anti-PD-L1 +anti-pd-l MB49 bladder carcinoma * * Days PBS apd1 +apd1

17 Enhancement of immunotherapeutic properties of through genetic engineering

18 upregulates a range of immune activating and inhibitory genes in tumors p-value (-Log10) PBS ICOS PDL1 PDL2 CD40 CD27 OX40 4-1BB CD28 PD1 GITR p = Fold Change (Log2)

19 Therapy with induces upregulation of inducible costimulator (ICOS) on TILs Activation/Proliferation T cell CTLA-4 ICOS ICOSL m M u m u m M u m u TCR MHC-peptide M M APC Antigen presentation and co-stimulation Sustained ICOS upregulation on peripheral CD4 lymphocytes is strongly correlated with clinical benefit from anti-ctla-4 therapy (Carthon et al. Clin Cancer Res 2010)

20 Expression of ICOSL transgene from in mouse and human cell lines Zamarin D, Wolchok JD, Allison JP. Submitted

21 -ICOSL in combination with CTLA-4 blockade leads to superior efficacy in tumor models susceptible to B16-F10 MB49 CT26 Zamarin D, Wolchok JD, Allison JP. Submitted

22 Summary and model Tumor rejection Anti-PD-1 No response Tumors Anti- CTLA-4 T cell Anti- PD-L1 Response MHC, B7-1,2 APC PBS No response virus Co-stimulatory ligands Response

23 Acknowledgements Memorial Sloan Kettering Cancer Center, New York, NY Jedd D. Wolchok Taha Merghoub Gopa Iyer Rikke Holmgaard Jacob Ricca Tamar Plitt Brian Ko Anton Oseledchyk MD Anderson Cancer Center, Houston, Tx James P. Allison Padmanee Sharma Icahn School of Medicine at Mount Sinai, New York, NY Peter Palese Adolfo Garcia-Sastre

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