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Pancreatic CancerImmunotherapy
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Lawrence et al. Nature 2013
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Foley et al. Cancer Letters 2015Hilmi, Bartholin & Neuzillet. World J Gastroenterol 2018
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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
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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
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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.
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Lee & Gibbs. J pers Med 2019
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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
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Pushalka et al. Cancer Discov 2018
• Gut Microbiota educates the Immune System and Modulates Carcinogenesis
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Nywening et al. Lancet Oncol 2016
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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
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Impact of IDO1 immunometabolism in cancer
Prendegast et al. Cancer Res 20187
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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
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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
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Naing et al. J Clin Oncol 2016
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MMRd/MSI-H Pancreatic CancerM7824 = Bifunctional fusion protein IgG1-antiPD1 + anti-TGFB
Guley et al. ASCO 2017
Hilmi, Bartholin & Neuzillet. World J Gastroenterol 2018
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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
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Torphy. Ann Gastroenterol Surg 2018
Desmoplastic stroma of pancreatic cancer
Looi et al. J Exp Clin Cancer Res 2019
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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
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Banerjee et al. Cancer Lett 2018
Tumor Associated Antigens most frequently targeted in PC Immunotherapy
Claudin 18.2
Ali et al. Front Oncol 2019
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Pancreatic CancerMesothelin-specific CAR T cell therapy
Beatty & O'Hara. Cancer Immunol Res 2014;
Liver CR
Primary PDAC PD
Tumor heterogeneity: mixed clinical response
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Exosomes and the Future of Immunotherapy in Pancreatic Cancer
Batista & Melo. Int J Mol Sc 2019
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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)
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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
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Hilmi, Bartholin & Neuzillet. World J Gastroenterol 2018
Oncolytic Virus & Pancreatic Cancer
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Mahmood et al. Cancers 2018
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LAPC: Irreversible Electroporation + Allogeneic NK cell immunotherapy
Mahmood et al. Cancers 2018
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©Evgenia Arbugaeva
Conclusions
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Morrison, Byrne & Vonderheide. Trends Cancer 2018
Mechanisms of Immunotherapies in Pancreatic Ductal Adenocarcinoma
Zhang et al. Cancers 2018
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Morrison, Byrne & Vonderheide. Trends Cancer 2018
Clinical Status of Immunotherapies in Pancreatic Cancer
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“… aún en los dominios al parecer más trillados
quedan todavía muchas incógnitas por
despejar”
S. Ramón y Cajal