Targeting B cells in pancreatic adenocarcinoma: does RESOLVE resolve the question?

In this issue of Annals Oncology, Tempero et al.1Tempero M. Oh D.-Y. Tabernero J. al.Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment patients metastatic pancreatic adenocarcinoma: phase III RESOLVE Study.Ann Oncol. 2021; 32: 600-608Abstract Full Text PDF Scopus (19) Google Scholar report results the trial ibrutinib added to ductal adenocarcinoma (PDAC). global 424 patients, there was no survival benefit addition ibrutinib. Moreover, were numerical trends worse outcome experimental arm on most secondary endpoint analyses. joins a growing number negative trials PDAC. We continue struggle translating encouraging pre-clinical findings into improved The median such remains <12 months, very disturbing statistic. It is therefore important reflect see why we consistently fail deadly disease. Targeting tumor microenvironment (TME) currently rational strategy developing new therapies PDAC offers exciting translational research opportunities. Pre-clinical evidence supported targeting Bruton's tyrosine kinase (BTK) disrupt B-cell function animal models through multiple mechanisms including stromal reaction2Minici R.E. Lanzillotta Monno A. al.B lymphocytes contribute reaction adenocarcinoma.Oncoimmunology. 2020; 9: 1794359Crossref PubMed (6) immune modulation.3Roghanian Fraser C. Kleyman cells promote tumorigenesis.Cancer Discov. 2016; 6: 230-232Crossref (30) Scholar,4Das S. Bar-Sagi D. BTK signaling drives CD1d(hi)CD5(+) regulatory differentiation carcinogenesis.Oncogene. 2019; 38: 3316-3324Crossref (27) not clear which, if any, are applicable human Interfering malignant B may be different than PDAC's microenvironment. from spleen thought those that reside TME.5Spear Candido J.B. McDermott J.R. al.Discrepancies spontaneous orthotopic murine cancer uncover immunostimulatory phenotype cells.Front Immunol. 10: 542Crossref (39) information consistent role carcinogenesis progression. There also data supporting their enhancing antitumor response,5Spear recent reports showing an association infiltration longer PDAC.6Castino G.F. Cortese N. Capretti G. al.Spatial distribution predicts prognosis 2015; 5: e1085147Crossref (94) Scholar,7Brunner Maier K. Rümmele P. al.Upregulation CD20 positive B-cells aggregates zone associated better adenocarcinoma.Int J Mol Sci. 21: 1779Crossref (13) These uncertainties raise question whether scientific supports PDAC, especially as single biological agent absence any hypothesis patient selection. reality that, presence dynamic complex TME disruption biology resulting clinical by alone indeed unlikely. fact, other molecule or pathway vast majority studies founded between molecular target behavior (phenotype). Unfortunately, current do faithfully recapitulate TME. Hypotheses underlie drug testing well detached reality. surprising all have been failures, exception poly(ADP-ribose) polymerase inhibition which based firm phenotype–genotype association.8Golan T. Colombo Scambia B.-G. al.Maintenance olaparib newly diagnosed advanced ovarian cancer.N Engl Med. 381: 317-327Crossref (765) Identification must come comprehensive investigation alongside experiments relevant discover robust rationale. underscores need higher level scrutiny launching trial. consensus how advance single-arm, small pilot I/II costly reasonable chance success. Understandably, decisions development influenced urgent therapies, lowers threshold moving forward. would signals initial population will sufficient launch PDAC? Ib study attempted explore modulatory effects PDAC.9Sinha Betts Griffith al.Immune (abstract P-146).Ann 30: iv40Abstract Another significantly lower cumulative exposure cytotoxic agents arm, suggesting less tolerated, efficacious, both, when compared control arm. further emphasizes downside insufficient evaluation combinations before setting. A formal always precede III, only detect efficacy but establish tolerability dose optimization combination, unless compelling science early justifies forgoing II embarking Negative oncology provide invaluable knowledge disease biology, exception. much like learn more did succeed despite expectations. interested know engaged closely perturbations related ibrutinib's pharmacodynamics. Based track record failed concern dampen even end and/or worthy exploration, TME-targeting agents.10Zhao Y. Shen Feng al.Regulatory induced cell-derived interleukin-18 tolerance via PD-1/PD-L1 pathway.Oncotarget. 2017; 14803-14814Crossref Scholar,11Schwartz Zhang Rosenblatt J.D. cell regulation anti-tumor response carcinogenesis.J Immunother Cancer. 4: 40Crossref (132) Treatments enhance T-cell activity inclusion inhibitory treatment12Gunderson A.J. Kaneda M.M. Tsujikawa al.Bruton kinase-dependent cross-talk pancreas cancer.Cancer 270-285Crossref (290) Scholar,13Tong D.N. Guan Sun J.H. al.Characterization cell-mediated interaction patients.Clin Exp Pharmacol Physiol. 47: 1342-1349Crossref (4) confirming exclusion.14Mirlekar B. Michaud Lee S.J. IL35 STAT3-dependent CD8(+) exclusion Immunol Res. 8: 292-308Crossref (21) should test beyond BTK.15Burger J.A. Wiestner receptor signalling cancer: preclinical advances.Nat Rev 2018; 18: 148-167Crossref (152) Work dissect roles subsets define who optimize drugs modulators.6Castino Scholar,16Ligeiro Rao Maia Cells gastrointestinal focus opportunities precision medicine?.Adv Med Biol. 1273: 175-195Crossref (2) conclusion, resolve field modulating widely open increasing Success future largely depend characterization TME, judicious use models, design.