pancreatic cancer · 2019. 6. 28. · tmb 21.1 mt/mb msi-h tmb 50.2 mt/mb msi-h mmr-d pancreatic...
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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