Pancreatic CancerImmunotherapy

Lawrence et al. Nature 2013

Foley et al. Cancer Letters 2015Hilmi, Bartholin & Neuzillet. World J Gastroenterol 2018

Pancreatic CancerMMR-D / MSI-High

• MSI-H in < 0.5 - 1% PDAC1, 2

• BRCA / PALB1 mutations ≈ 7-10% PDAC3

PARPi (may further induce genomic instability) + ICPi combinations ?

1Lawrence et al. Cancer 2017; 2Humphis et al. Gastroenterology 2017; 3Sahin et al. Expert Rev Gastroenterol Hepatol 2016

TMB 21.1 mt/MB

MSI-H

TMB 50.2 mt/MB

MSI-H

MMR-D Pancreatic Cancer Acquired Resistance to Immunotherapy

Hu et al. J Immunother Cancer 2018

45 y woman LAPC MMR-D

FOLFIRINOX and stereotactic

body RT

anti-PD-L1 + IDO1 inhibitor

SD x 3 months PR x 22 months

Surgery: M1 endometrium and left ovary

anti-PD-L1

Florid CD8+ T infiltrating tumor & stroma

MLH1 (-) PMS2 (-)

Prominent PD-1 positive immune cells PD-L1+ focally present in IC and in some TC

Immune Profiling of Metastatic Pancreatic Adenocarcinoma

Hu et al. J Immunother Cancer 2018

• mKRAS G12D and mRNF43 G659Vfs*41 were retained from

the pre-treatment tumor in the treatment-resistant tumor.

• No copy number alterations were detected in either the pre-

treatment or the acquired resistance tumor sample.

• No loss-of-function mutations or LOH in the HLA genes, B2M,

PTEN, JAK1, JAK2, or TAP1.

Lee & Gibbs. J pers Med 2019

Pancreatic Cancer Immunosuppresive Microenvironment

CXCR2

Galectin-1

Treg

CD4 T-cell

CD8 T-cell

TAMsCXCR2

CSF1R

Modificado de Balachandran, Beatty & Dugan. Gastroenterollogy 2019

myCAF

iCAF

MoMDSC GrMDSC

Pushalka et al. Cancer Discov 2018

• Gut Microbiota educates the Immune System and Modulates Carcinogenesis

Nywening et al. Lancet Oncol 2016

Combination of aCD40/chemotherapy induces T-cell immunity, overcomes resistance to PD-1and CTLA-4 blockade and improves survival in KPC genetic model of PDAC.

Winograd et al. Cancer Immunol Res 2015

Pancreatic CancerCD40 agonists

CD40 agonists re-educate MDSC to acquire antitumor properties

Impact of IDO1 immunometabolism in cancer

Prendegast et al. Cancer Res 20187

Impact of IDO1 immunometabolism in cancer

Prendegast et al. Cancer Res 20187

INDOXIMOD + nab-P/Gemc ORR 37% (11/30)

Peng et al. BMC Cancer 2014; Nathan et al. ASCO 2016

Prediagnostic Plasma 25-Hydroxyvitamin D and Pancreatic Cancer Survival

Yuan et al. J Clin Oncol 2016; Aranov. J Investig Med 2011; Norman. Circ Res 2014

Vitamin D can modulate the innate and adaptive immune responses

Naing et al. J Clin Oncol 2016

MMRd/MSI-H Pancreatic CancerM7824 = Bifunctional fusion protein IgG1-antiPD1 + anti-TGFB

Guley et al. ASCO 2017

Hilmi, Bartholin & Neuzillet. World J Gastroenterol 2018

Modeling Pancreatic Cancer Dynamics with Immunotherapy

Hu, Ke & Jang. Bull Math Biol 2019

- Mono-immunotherapy is unlikely to control pancreatic cancer

- Combined immunotherapies between anti-TGF-𝛽 and adoptive transfers of immune cells can prolong patient survival

Torphy. Ann Gastroenterol Surg 2018

Desmoplastic stroma of pancreatic cancer

Looi et al. J Exp Clin Cancer Res 2019

Simeonides, Anderton & Serres. J Immunoth Cancer 2017

Focal Adhesion Kinase Inhibitors (FAKi) open the door to CPI in PaCa

Reprogramming the fibrotic and immuno-suppressive pancreatic TME

Banerjee et al. Cancer Lett 2018

Tumor Associated Antigens most frequently targeted in PC Immunotherapy

Claudin 18.2

Ali et al. Front Oncol 2019

Pancreatic CancerMesothelin-specific CAR T cell therapy

Beatty & O'Hara. Cancer Immunol Res 2014;

Liver CR

Primary PDAC PD

Tumor heterogeneity: mixed clinical response

Exosomes and the Future of Immunotherapy in Pancreatic Cancer

Batista & Melo. Int J Mol Sc 2019

Pancreatic CancerVaccines

1 Middleton et al. Lancet Oncol 2014; 2 Biotech et al. Press releas 2016; 3 IMPRESS NGs. Press Release 2016

(1)

(2)

(3)

Pancreatic CancerVaccine + ICPi

Ssoares et al. J Immunother 2015; Le at al. J Clin Onc 2015; Sahin et al. Ann Oncol 2017

Vaccine therapy facilitates effector T cell infiltration into PDAC

No OS benefit, however some biologic effect exists

Hilmi, Bartholin & Neuzillet. World J Gastroenterol 2018

Oncolytic Virus & Pancreatic Cancer

Mahmood et al. Cancers 2018

LAPC: Irreversible Electroporation + Allogeneic NK cell immunotherapy

Mahmood et al. Cancers 2018

©Evgenia Arbugaeva

Conclusions

Morrison, Byrne & Vonderheide. Trends Cancer 2018

Mechanisms of Immunotherapies in Pancreatic Ductal Adenocarcinoma

Zhang et al. Cancers 2018

Morrison, Byrne & Vonderheide. Trends Cancer 2018

Clinical Status of Immunotherapies in Pancreatic Cancer

“… aún en los dominios al parecer más trillados

quedan todavía muchas incógnitas por

despejar”

S. Ramón y Cajal