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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 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 2
  3. 3. TME Biophysical Properties 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? 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 ... 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 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? 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 8 Halozyme investor day presentation 7 January 2015
  9. 9. A note regarding HA (hyaluronan) 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 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 24 There is much to learn stay tuned
  25. 25. Paul D Rennert on Twitter @PDRennert 1-508-282-6370 (USA)
  26. 26. Backup slide: IDO combination with HA