Im vacs 2015 rennert v2

Immunomodulatory Targets in the Tumor Microenvironment

ImVACS, 24 August 2015

www.sugarconebiotech.com 1

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


TME Biophysical Properties


•  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

TME Cellularity – who lives here?


- 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?

Other Attributes: The TME ...


•  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

Pancreatic TME as an instructive example


•  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

Why Focus on Pancreatic Cancer?


•  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

TME extracellular matrix (ECM) composition and median survival in pancreatic cancer


Halozyme investor day presentation 7 January 2015

A note regarding HA (hyaluronan)


•  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.

One more ... hyaluronidase treatment


Halozyme investor day presentation 7 January 2015

•  destroying the HA component of the ECM with pegylated-HA allows therapeutics better access to the tumor


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.


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...


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 immunosuppressive 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)


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.


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....


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).


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.


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?


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.


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

CIR 2015 in press

Salmonella – shIDO – PEGPH20, KPC orthotopic pancan model

with increased proinflammatory cytokines produced


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


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...


There is much to learn

stay tuned

Paul D Rennert www.sugarconebiotech.com

[email protected] on Twitter @PDRennert 1-508-282-6370 (USA)

www.sugarconebiotech.com

Backup slide: IDO combination with HA

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Im vacs 2015 rennert v2

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