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Im vacs 2015 rennert v2

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Some cancers are very resistant to immunotherapy. Here I talk about two of those, and speculate on the role of the tumor microenvironment in blocking productive anti-tumor immunity.

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Im vacs 2015 rennert v2

  1. 1. Immunomodulatory Targets in the Tumor Microenvironment ImVACS, 24 August 2015   www.sugarconebiotech.com 1
  2. 2. The Tumor Microenvironment (TME) •  The TME -  biophysical properties -  cellularity •  Why is it important? -  the link to metastasis -  the concept of zoning •  Example of targets and their potential for combinations with immune checkpoints www.sugarconebiotech.com 2
  3. 3. TME Biophysical Properties www.sugarconebiotech.com 3 •  ECM rich (collagen, HA) •  High intersitial pressure •  Poor penetrance (vascular, interstitial space) •  Hypoxia •  Necrosis •  Acidic (Lactic acid) Aberrant expression of cellular mediators -  growth factors -  cytokines & chemokines -  tryptophan -  adenosine figure courtesy Chris Thanos, Halozyme cartoon of a pancreatic tumor
  4. 4. TME Cellularity – who lives here? www.sugarconebiotech.com 4 - Cell populations: friend, foe or both? - More friends than foes = the tumor is winning - Why: immune subversion and evasion Macrophage - effector or TAM? Lymphoctye - Teffector or Treg? - NK? Fibroblast - resident (activated)? - CAF? Myeloid lineage - MDSC? - iDC? - monocytes?
  5. 5. Other Attributes: The TME ... www.sugarconebiotech.com 5 •  Is immunosuppressive •  Can confer therapy resistance -  anti-apoptotic niches (e.g. in bone marrow) -  refugia for cancer stems cells -  shelter from selective pressure (treatment resistance) •  Supports metastasis – resistance >>> metastasis •  Remodels metastatic niches (Ovarian cancer example) •  Is highly diverse – within indications, between stages of an indication (early, advanced, metastasis), across tumor types, between patients •  We currently underappreciate this compexity, meaning we are at a primitive level in understanding this field
  6. 6. Pancreatic TME as an instructive example www.sugarconebiotech.com 6 •  The fibrotic environment (desmoplasia) limits biophysical exchage: extracellular/ interstitial fluid, gases, proteins, metabolites •  abundant CAFs, collagen, hyaluronic acid (brown: ECM component) image courtesy of Chris Thanos, Halozyme HA Malignant cells Cancer associated fibroblasts Immune cells
  7. 7. Why Focus on Pancreatic Cancer? www.sugarconebiotech.com 7 •  Huge unmet need: Incidence and Mortality -  US: 46,000 diagnosed/yr; 39,000 deaths. Worldwide: x10 or more... -  Rising incidence: incidence and mortality may double by 2030. -  90% of diagnoses are for the highly lethal ductal adenocarcinoma (PDAC) -  Pancreatic cancer is the only cancer with a 5-year OS rate in the single digits (6%). Most patients (~80%) die the first year. -  If disease is localized, the 5-year OS is 22%. -  However, >50% of patients are diagnosed with disseminated disease, having a 5-year OS of 2%. •  Some modest successes with vaccination attempts (GVAX etc) suggests that inducing an immune responses is possible •  No to little success to date with immune checkpoint monotherapy
  8. 8. TME extracellular matrix (ECM) composition and median survival in pancreatic cancer www.sugarconebiotech.com 8 Halozyme investor day presentation 7 January 2015
  9. 9. A note regarding HA (hyaluronan) www.sugarconebiotech.com 9 •  A major component of ECM and a very large glycosaminoglycan (MW often measured in the millions). •  HA is remarkably viscous in physiological fluids (10 mg/ml has a viscosity 5000x that of water) while retaining elastisity - this is why it is used, although with limited success, in treating degraded joints. •  HA contributes to a variety of cancer cell activities including cell proliferation and migration, and in the case of pancreatic cancer appears to act in part as a physical barrier, creating a gated community with it's own, internal, zoning bylaws in certain cancers, including pancreatic. •  At least 14 fourteen carcinoma types have elevated HA levels in the tumor cells or the surrounding stroma or both. •  In ovarian cancer, the correlation between HA level and progression is sufficient to support the use of HA concentration as a prognostic marker.
  10. 10. One more ... hyaluronidase treatment www.sugarconebiotech.com 10 Halozyme investor day presentation 7 January 2015 •  destroying the HA component of the ECM with pegylated-HA allows therapeutics better access to the tumor
  11. 11. www.sugarconebiotech.com 11 Pancreatic mets may phenocopy the 1o tumor •  At least in some pancreatic cancer patients the mets resemble the primary tumor in ECM composition Whatcott et al. 2015. Clin Cancer Res; 21(15); 3561–3568.
  12. 12. www.sugarconebiotech.com 12 What does this tell us? •  For encapsulated solid tumors like pancreatic cancer TME integrity is fundamental to tumor health. •  Questions we should ask about this example: -  what happens molecularly when the tumor architecture crumbles? -  how does the immune system respond? -  how does the tumor crawl back to life? •  What additional targets can increase efficacy? •  What targets within the TME are broadly useful? -  Hyaluronidase only useful in certain indications with very high HA contect. •  Can we model the TME across indications or within diverse indications? •  OK, moving on...
  13. 13. www.sugarconebiotech.com 13 Targets Within the TME •  Within the TME, local factors take control of the community: tumor zoning bylaws •  These factors have diverse sources and enforce zoning in myriad ways -  all have immuno- suppressive properties -  cells can both generate and respond to these factors -  several of these targets are being aggressively developed •  CSF-1 Mahoney, Rennert, Freeman NRDD 14: 561–584 (August 2015)
  14. 14. www.sugarconebiotech.com 14 Ovarian Cancer as a model for TME-remodeling and metastasis •  Primary ovarian cancer is treated by debulking surgery, either preceded by (neoadjuvant) or followed by platinum-based chemotherapy. 5 year OS is ~30%. •  At diagnosis, about two thirds of patients will have peritoneal metastases. Peritoneal met bulk quickly surpasses primary tumor bulk, and tumor burden is inversely associated with survival. •  Platinum-resistant recurrent and metastatic disease may be treated with a different chemo-combo plus the anti-VEGF mAb bevacizumab (Phase 3). •  So a potential path forward in ovarian cancer is to control the return of mets following therapy, i.e. can we change the zoning bylaws before the tumor rebuilds? •  First we have to understand the peritoneal metastatic niche.
  15. 15. www.sugarconebiotech.com 15 Ovarian Mets as a TME model Initial steps are understood, yielding both biology and targets: migration of neoplastic and accessory cells, remodeling of ECM, and expansion of vasculature •  Transit of seeding cells into the peritoneum can be passive, but is enhanced by CXCR4, VEGF, LPA and VCAM-1. •  Engagement of mesothelial cell layer requires ECM proteins and CD44 (the HA receptor) to anchor, and proteases to fragment fibronectin and vitronectin and allow alpha integrin attachment: remodeling begins with those activated integrins... •  Alpha integrin activattion (by LPA etc) in turn activates TGFβ. TGFβ, VEGF, and diverse chemokines cooperatively set up a proangiogenic and immuno-suppressive cascade. •  As immune cells respond, CD8+ T and NK cell secretion of IFNγ induces IDO expression, further propagating immunosuppression. •  In the meantime, abundant CXCL12 and CSF-1 expression recruits immature myeloid cells, fostering the development of the MDSC population •  Thus, Zoning Bylaws are established....
  16. 16. www.sugarconebiotech.com 16 Ovarian Cancer and immunotherapy •  However, some ovarian cancer patients can respond to immunotherapy, as we have learned over the last few years: •  ipilimumab (anti-CTLA4, intermittent dosing) + GVAX in metastatic ovarian cancer. -  ORR 9% (n = 11). Hodi et al. 2008. Proc Natl Acad Sci U S A. 2008: 105:3005-3010. •  nivolumab (anti-PD-1, 1 or 3 mpk q3w) in platinum-resistant ovarian cancer. -  ORR 23% (n = 13). J Clin Oncol 32:5s, 2014 (suppl; abstr 5511). •  avelumab (anti-PD-L1, 10mpk q2w) in recurrent or refractory ovarian cancer. -  ORR 10.5% (n=75). J Clin Oncol 33, 2015 (suppl; abstr 5509). •  pembrolizumab (anti-PD-1, 10mpk q2w) in PD-L1+ refractoy ovarian cancer. -  ORR = 11.5% (n=26). J Clin Oncol 33, 2015 (suppl; abstr 5510).
  17. 17. www.sugarconebiotech.com 17 Ovarian Metastases Illustrate One Type of Zoning Some Ovarian cancers: Most Pancreatic cancers: Active immunsuppression Gated community Gajewski, Schreiber & Fu. 2013. Nat. Immunol. 14: 1014-1023.
  18. 18. www.sugarconebiotech.com 18 What should we look for.... •  IHC can tell us if CD8+ T cells are present in a tumor section, and perhaps some microenvironment data •  Additional useful information about the community and its zoning bylaws might include: -  Immunosuppressive cellularity: Tregs, MDSC, TAM -  T cell responsiveness (IFNγ) and TCR clonality -  Immunosuppressive factors: IDO, adenosine, LPA -  resistance markers: CXCR4 -  abundance of other targets e.g. VEGF •  What holds down responses in ovarian cancer?
  19. 19. www.sugarconebiotech.com 19 Immunosuppressive environment in ovarian cancer •  The TAM population (M2-type macrophages) is abundant and orchestrates immunosuppression by secreting CCL21 and attracting Tregs. The presence of Tregs is associated with poor prognosis and reduced OS in ovarian cancer. •  IDO is copiously produced by TAM/MDSC in ovarian cancer and regulates the balance between T effector cells and Treg cells in favor of the Tregs, via multiple mechanisms. -  Increased tumor burden (which entails the development of intratumoral hypoxia), further drives IDO expression. -  High IDO expression correlates with poor outcome in ovarian cancer (also endometrial, colon, melanoma, AML). •  PD-L1 expression on TAM, MDSC and tumor cells, and PD-1 expression on T cells, is also associated with poor prognosis in ovarian cancer •  TAM can be depleted from the tumor microenvironment by blockade of the CSF1R pathway.
  20. 20. www.sugarconebiotech.com 20 IDO on the horizon target therapeutic developer partners summary IDO INCB24360 Incyte AZN/ Medimmune combo with MEDI4736 (anti- PDL1), adv solid tumors including pancreatic cancer IDO INCB24360 Incyte BMS combo with nivolumab (anti-PD1), adv solid tumors including ovarian cancer IDO INCB24360 Incyte Roche/ Genentech combo with MPDL3280A (anti- PDL1) for NSCLC IDO INCB24360 Incyte Merck combo with MK-3475 (anti-PDL1) in NSCLC and advanced solid tumors IDO & TDO F001287 Flexus BMS buy-out; combination regimens with immunotherapies IDO NLG919 NewLink Roche/ Genentech combos with MPDL3280A (anti- PDL1) and novel therapies
  21. 21. CIR 2015 in press Salmonella – shIDO – PEGPH20, KPC orthotopic pancan model with increased proinflammatory cytokines produced
  22. 22. www.sugarconebiotech.com 22 Anti-CSF1R on the horizon target therapeutic developer partners summary anti- CSF1R FPA008 FivePrime BMS combo with nivolumab (anti-PD-1) in 6 cancer indications including pancreatic cancer anti- CSF1R emactuzumab Roche - combo with MPDL3280A (anti-PDL1) in 5 cancer indications including ovarian cancer anti- CSF1R IMC-CS4 Eli Lilly - Phase 1 monotherapy: breast and prostate cancers CSF1R inhibitor JNJ-40346527 J&J - heme malignancies CSF1R inhibitor PLX3397 Plexxikon/ Daaichi Merck combo with pembrolizumab in advanced solid tumors CSF1R inhibitor BLZ945 Sloan Kettering RI/Novartis - ongoing? CSF1R inhibitor AZD6495 Astra Zeneca - open innovation
  23. 23. www.sugarconebiotech.com 23 What can we expect •  Monotherapies will give no or modest response rates in these difficult cancers •  Combo therapies require an understanding of complex mechanisms employed in tumor defense, a defence that includes the TME •  For ovarian cancer there is clear hope, as the response rates acheived, while low, offer a glimpse of what may be achieved in combos •  For pancreatic cancer the challenge is to "tear down that wall" and certainly agents like PEGPH20 are only part of the answer •  IDO and CSF1R are promising targets ... there are many others •  Finally...
  24. 24. www.sugarconebiotech.com 24 There is much to learn stay tuned
  25. 25. Paul D Rennert www.sugarconebiotech.com rennertp@sugarconebiotech.com on Twitter @PDRennert 1-508-282-6370 (USA)
  26. 26. www.sugarconebiotech.com Backup slide: IDO combination with HA

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