Faculty Bibliography

Hepato-pancreatico-biliary (HPB) malignancies are difficult-to-treat and continue to to have a high mortality and significant therapeutic resistance to standard therapies. Immune oncology (IO) therapies have demonstrated efficacy in several solid malignancies when combined with chemotherapy, whereas response rates in pancreatic ductal adenocarcinoma (PDA) are poor. While promising in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), there remains an unmet need to fully leverage IO therapies to treat HPB tumors. We therefore defined T cell subsets in the tumor microenvironment of HPB patients utilizing a novel, multiparameter flow cytometry and bioinformatics analysis. Our findings quantify the T cell phenotypic states in relation to checkpoint receptor expression. We demonstrate the presence of CD103⁺ tissue resident memory T cells (T_RM), CCR7⁺ central memory T cells, and CD57⁺ terminally differentiated effector cells across all HPB cancers, while the anti-tumor function was dampened by expression of multiple co-inhibitory checkpoint receptors. Terminally exhausted T cells lacking co-stimulatory receptors were more prevalent in PDA, whereas partially exhausted T cells expressing both co-inhibitory and co-stimulatory receptors were most prevalent in HCC, especially in early stage. HCC patients had significantly higher T_RM with a phenotype that could confer restored activation in response to immune checkpoint therapies. Further, we found a lack of robust alteration in T cell activation state or checkpoint expression in response to chemotherapy in PDA patients. These results support that HCC patients might benefit most from combined checkpoint therapies, whereas efforts other than cytotoxic chemotherapy will likely be necessary to increase overall T cell activation in CCA and PDA for future clinical development.

[This corrects the article DOI: 10.3389/fimmu.2023.1067352.].

ABSTRACT/UNASSIGNED:Papillary dermal elastolysis has been described in the setting of experimental combination nivolumab and cabiralizumab immunotherapy. We report a third patient with distinctive, generalized atrophic macules that developed after a morbilliform eruption during a clinical trial for treatment of metastatic pancreatic adenocarcinoma. Histopathological findings demonstrated diminished elastic fibers in the papillary dermis, associated with a histiocyte-rich infiltrate and increased dermal mucin, features that should clue the dermatopathologist to this condition.

Tumor genotype can influence the immune microenvironment, which plays a critical role in cancer development and therapy resistance. However, the immune effects of gain-of-function Trp53 mutations have not been defined in pancreatic cancer. We compare the immune profiles generated by Kras^G12D-mutated mouse pancreatic ductal epithelial cells (PDECs) engineered genetically to express the Trp53^R172H mutation with their p53 wild-type control. Kras^G12D/+;Trp53^R172H/+ tumors have a distinct immune profile characterized by an influx of CD11b⁺Ly6G⁺ neutrophils and concomitant decreases in CD3⁺ T cells, CD8⁺ T cells, and CD4⁺ T helper 1 cells. Knockdown of CXCL2, a neutrophil chemokine, in the tumor epithelial compartment of CRISPR Kras^G12D/+;Trp53^R172H/+ PDEC tumors reverses the neutrophil phenotype. Neutrophil depletion of mice bearing CRISPR Kras^G12D/+;Trp53^R172H/+ tumors augments sensitivity to combined CD40 immunotherapy and chemotherapy. These data link Trp53^R172H to the presence of intratumoral neutrophils in pancreatic cancer and suggest that tumor genotypes could inform selection of affected individuals for immunotherapy.

Background: Tyrosine kinase inhibitors can prolong survival in advanced HCC patients, but response rates have been minimal. Recently, immune checkpoint inhibition with nivolumab (nivo) demonstrated objective response rates (ORR) of 15% (escalation phase) and 20% (expansion phase) in the Checkmate 040 study. Pre-clinical and translational studies have demonstrated that IL-8 and tumor associated macrophages (TAMs) contribute to HCC progression and recurrence following treatment. Therefore, rationale exists to evaluate combinatorial approaches to target TAM function combined with checkpoint inhibitory therapy. This phase II, randomized study will evaluate the safety and efficacy of combined anti-CSF1R (Cabiralizumab) or anti-IL-8 (BMS-986253) in combination with Nivo in advanced HCC. Method(s): Advanced HCC patients without prior systemic treatment and disease measurable by RECISTv1.1 with Childs A liver function are eligible. Patients will be enrolled (n=25 per arm) to Nivo 240 mg IV Q2 weeks monotherapy, Nivo 240 mg IV + BMS-986253 1200 mg IV Q2 weeks, or Nivo 240 mg IV + Cabiralizumab 4 mg/kg IV Q2 weeks. Primary endpoints include safety and ORR determined by RECISTv1.1. Secondary endpoints include time to response, duration of response, progression free survival, and overall survival. Exploratory endpoints include analysis of tumor microenvironment immune and tumor cell profiling of pre- and on-treatment tumor tissue

Background: Preoperative chemoRT is a standardof- care as shown in the CROSS trial (N Engl J Med 2012;366:2074-2084), Surgery is sometimes deferred in pts with clinical CR (cCR) based on lack of overall survival benefit (J Clin Oncol 2005;23:2310-2317, J Clin Oncol2007;25:1160-1168). Nivolumab has activity in advanced ESCC (Lancet Oncol 2017;18:631-639), and adding it to chemoRT may improve outcomes.
Method(s): This phase I/II study was designed to assess the safety and tolerability and efficacy of nivolumab added to chemoRT (6 weekly carboplatin AUC 2, paclitaxel 50mg/m2, RT 50.4 Gy in 1.8 Gy fractions 5/7 days) for pts with TanyN1-3 or T3-4N0M0 ESCC. The phase I primary endpoint is 'unacceptable toxicity' at 28 days after the last dose of chemotherapy. The phase II primary endpoints are cCR (endoscopy + PET/CT) and pCR rates for pts undergoing surgery. Nivolumab is given q2W x2, then concurrent chemoRT with nivolumab q2W x3. If no cCR, pt proceeds to esophagectomy, then adjuvant nivolumab q2W x3; if cCR, pt has an option of no surgery but receives nivolumab q2W x3.
Result(s):From 7/20/17 to 12/27/18, 6 pts were enrolled. No unacceptable or grade 5 toxicities were observed. The most common grade 1/2 AEs in >1 pt were anorexia, myelosuppression, elevated AST and nausea. Grade 3/4 AEs in >1 pt were lymphopenia and leukocytopenia. 2 pts required hospitalizations (dyspnea 1, colitis 1). All pts completed therapy; 1 pt had dose delay due to grade 2 esophagitis; 2 pts progressed, 4 achieved cCR. Of 4 pts with cCR, 2 pts chose surgery and both achieved pCR. None of the 4 pts recurred.
Conclusion(s): ChemoRT with nivolumab is tolerable with manageable toxicities in locally advanced ESCC. Enrollment to the phase II portion ended because of slow accrual. Adverse Events. Grade 1 &2 in > 1 pt: 4/6: Anorexia & Anemia 3/6: Leukocytopenia Neutropenia Thrombocytopenia Nausea & Elevated AST 2/6: Hypomagnesemia Hypokalemia Grade 3 & 4 in > 1 pt: 5/6: Lymphopenia, 2/6: Leukocytopenia

Pancreatic cancer is a devastating disease that is largely refractory to currently available treatment strategies. Therapeutic resistance is partially attributed to the dense stromal reaction of PDAC tumors that includes a pervasive infiltration of immunosuppressive (M2) macrophages. Nab-paclitaxel (trade name Abraxane) is a nanoparticle albumin-bound formulation of paclitaxel that, in combination with gemcitabine, is currently the first line treatment for pancreatic cancer. Here, we show that macrophages internalized nab-paclitaxel via macropinocytosis. The macropinocytic uptake of nab-paclitaxel induced macrophage immunostimulatory (M1) cytokine expression and synergized with IFNgamma to promote inducible nitric oxide synthase (iNOS) expression in a TLR4-dependent manner. Nab-paclitaxel was internalized by tumor-associated macrophages in vivo, and therapeutic doses of nab-paclitaxel alone, and in combination with gemcitabine, increased the MHCII+CD80+CD86+ M1 macrophage population. These data revealed an unanticipated role for nab-paclitaxel in macrophage activation and rationalize its potential use to target immune evasion in pancreatic cancer.