Author Correction: Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment
Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.
Prospective BASECAMP-1 experience in patients with gastrointestinal (GI) cancer: Identifying patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) for a future therapeutic trial exploiting LOH as a tumor vulnerability [Meeting Abstract]
Background: Metastatic colorectal (CRC), pancreatic (PANC), and gastroesophageal cancers are the leading causes of GI cancer-related mortality (5-y survival: 15%, 3%, and 5%-6%, respectively) (ACS 2022). HLA LOH is a recurrent mechanism of immune escape observed in 15%-20% of GI cancers (Hecht R., ASCO GI 2022). The Tmod platform is a logic-gated chimeric antigen receptor (CAR) T-cell modular system, comprising a carcinoembryonic antigen (CEA)- or mesothelin (MSLN)-targeting CAR activator and a separate HLA-A*02-targeting blocker receptor. Both in vitro/in vivo, Tmod CAR T therapy kills cells with HLA-A*02 LOH (tumor) without harming cells with retained HLA-A*02 expression (normal). However, HLA-A*02 LOH can only be therapeutically exploited if patients are identifiable through a feasible and timely clinical workflow.
Method(s): We established a biobanking protocol (BASECAMP-1, NCT04981119) to determine whether HLA-A*02 LOH patients can be prospectively identified. Patients with CRC, PANC, or non-small cell lung cancer (NSCLC), and a high risk for incurable relapse, were screened first using a standard HLA assay. Heterozygous HLAA* 02 positive tumor samples were then assessed for LOH using a bioinformatic algorithm applied via the Tempus xT platform.
Result(s): As of Sep 1, 2022, 83 patients were consented at 4 institutions. HLA status was obtained from 70 patients and 28 were identified as HLA-A*02:01 heterozygous (40%; expected frequency based on USA NMDP data, 27.6%). LOH results were available for 16 patients; 4 LOH-positive patients were identified (25%, 2 PANC, 2 NSCLC). The LOH assay sensitivity declines below a tumor purity of 40% (Hecht R., ASCO GI 2022). Six patients had a tumor purity of 20% (all with PANC, a tumor known for high stromal content), limiting possible LOH detection. The impact of tumor purity on LOH sensitivity was highlighted in a patient with a low initial sample tumor purity (30%) that resulted in a 41% probability of HLA-A*02:01 LOH (below positive threshold). A second sample with a higher tumor purity (70%), obtained from formalin-fixed, paraffin-embedded sections, resulted in a 92% probability of HLA-A*02:01 LOH (positive).
Conclusion(s): BASECAMP-1 prospective identification of HLA-A*02 LOH is feasible in the real-world setting. The frequencies of the HLA-A*02 allele and of HLA-A*02 LOH in this cohort mirrored expected population frequencies. LOH results can be obtained within a clinically feasible workflow and timeframe, although samples with a,40% tumor purity have a reduced sensitivity for LOH detection, an issue recurrently observed in patients with PANC. The BASECAMP-1 strategy enables prospective identification of appropriate patients for future therapeutic clinical trials using Tmod CEA and MSLN logic-gated CAR T cells
A phase 1b/2, open-label study of amivantamab monotherapy or in combination with standard-of-care chemotherapy in participants with advanced or metastatic colorectal cancer [Meeting Abstract]
Background: Amivantamab, a fully human EGFR and MET bispecific antibody, has shown clinical activity against tumors with primary activating EGFR mutations, EGFR resistance mutations, or MET pathway activation. Amivantamab has demonstrated activity in both EGFR- and MET-driven non-small cell lung cancer, with preclinical evidence demonstrating its ability to recruit immune effector cells. While two anti-EGFR antibodies are incorporated as part of the standard of care (SoC) for metastatic colorectal cancer (mCRC) patients, MET is highly expressed or amplified in subsets ofmCRC and additionally plays a role in mediating resistance to anti-EGFR therapies; therefore, amivantamab may provide benefit in this setting.
Method(s): This open-label, multicenter, global Ph1b/2 study will assess the safety and anti-tumor activity of amivantamab as a monotherapy and characterize the safety and tolerability of amivantamab in addition to SoC chemotherapy in KRAS, NRAS, BRAF, and EGFR ectodomain wild type participants with advanced or metastatic CRC. The Ph2 amivantamab monotherapy Cohorts A and B will assess the antitumor activity in participants with left-sided CRC who have progressed on or after SoC fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and an anti-VEGF treatment, without (Cohort A) or with (Cohort B) prior exposure to anti-EGFR treatment. The Ph2 amivantamab monotherapy Cohort C will assess the antitumor activity in participants with right-sided CRC who have progressed on or after SoC fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and an anti-VEGF treatment, with or without an anti-EGFR treatment. The Ph1b dose confirmation cohorts (Ph1b-D and Ph1b-E) will assess the safety and confirm the recommended Ph2 combination dose (RP2CD) of amivantamab in addition to SoC chemotherapy regimens (mFOLFOX6 or FOLFIRI). Upon confirmation of the RP2CD, the Ph2 Cohorts D and E, which are distinct cohorts from Ph1b-D or Ph1b-E, will further characterize the safety, tolerability, and preliminary anti-tumor activity of amivantamab in addition to SoCmFOLFOX6 or FOLFIRI in mCRC patients who have progressed after front-line therapy. The primary objectives are to assess the anti-tumor activity of amivantamab as a monotherapy and characterize the safety of amivantamab when added to SoC chemotherapy in participants with mCRC (Ph2 cohorts), as well as to assess the RP2CD of amivantamab when added to SoC chemotherapy (Ph1b). The key secondary objectives are to characterize the safety of amivantamab as a monotherapy and to assess the anti-tumor activity of amivantamab when added to SoC chemotherapy in participants with mCRC. This study is currently enrolling (NCT05379595) as of August 2022 in 12 countries, with goal enrollment of 225 participants
A multicenter, randomized phase II study of total neoadjuvant therapy (TNT) with FOLFIRINOX (FFX) and SBRT, with or without losartan (L) and nivolumab (N) in borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) [Meeting Abstract]
Background: Outcomes in BR and LA PDAC remain historically poor, in part due to low rates of R0 resection. A prior phase II study demonstrated that losartan (L) as a TGF-betaeta inhibitor combined with FOLFIRINOX (FFX) and radiation in LA PDAC led to a 61% R0 resection rate. Additionally, prior phase II studies suggest potential synergy with SBRT and nivolumab (N) in PDAC.We conducted a multi-center, randomized phase II trial to evaluate the effect of L and L+N in combination with TNT using FFX and SBRT.
Method(s): Patients with BR or LA PDAC by NCCN criteria, pathologically confirmed, ACE/ARB naive, were randomized to TNT with FFX and SBRT (Arm 1), TNT + L (Arm 2), and TNT+L+N (Arm 3), stratified by BR/LA. Patients already on an ACE or ARB were enrolled on an exploratory arm of TNT+N (Arm 4) and will be reported separately. TNT consisted of FFX x 8 followed by SBRT (6.6 Gy x 5). L was given at 50 mg qd throughout TNT and for 6mo after surgery. N was given at 240 mg flat dosing q2 wks concurrent with SBRT and for 12 doses postoperatively. All patients were recommended for surgical exploration after TNT. The study was designed to compare the R0 resection rate on each of Arms 2 and 3 independently versus Arm 1 at a one-sided 0.10 level. Secondary endpoints were PFS, OS, and pCR rates and analyzed using two-sided tests with Arm 1 as the control arm. Intent-to-treat analysis was based on eligible patients who started therapy on protocol.
Result(s): Patients with BR or LA PDAC by NCCN criteria, pathologically confirmed, ACE/ARB naive, were randomized to TNT with FFX and SBRT (Arm 1), TNT + L (Arm 2), and TNT+L+N (Arm 3), stratified by BR/LA. Patients already on an ACE or ARB were enrolled on an exploratory arm of TNT+N (Arm 4) and will be reported separately. TNT consisted of FFX x 8 followed by SBRT (6.6 Gy x 5). L was given at 50 mg qd throughout TNT and for 6 mo after surgery. N was given at 240 mg flat dosing q2 wks concurrent with SBRT and for 12 doses postoperatively. All patients were recommended for surgical exploration after TNT. The study was designed to compare the R0 resection rate on each of Arms 2 and 3 independently versus Arm 1 at a one-sided 0.10 level. Secondary endpoints were PFS, OS, and pCR rates and analyzed using two-sided tests with Arm 1 as the control arm. Intent-to-treat analysis was based on eligible patients who started therapy on protocol.
Conclusion(s): We did not observe effects of L and L+N on the R0 resection rate, PFS, OS, and pCR rate when added to TNT with FFX and SBRT for BR or LA PDAC. The lack of differences may reflect heterogeneity in surgical opinion as the decision for proceeding to surgery following TNT tends to be highly variable in a population with historically low resection rates
ONCX-NAV-G201: A phase 2 basket study of navicixizumab monotherapy or in combination with chemotherapy in patients with select advanced solid tumors-Colorectal Cancer Cohort (trial in progress) [Meeting Abstract]
Background: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors (NCT05453825). Cohort A will enroll colorectal cancer (CRC) patients. Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human deltalike ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aggressive CRC remains difficult to treat owing to the aberrant activation of oncogenic signaling pathways including the NOTCH pathway. Preclinical data show that co-inhibition of NOTCH and angiogenesis have superior antitumor activity compared to individual pathway inhibition. We postulate that navicixizumab will demonstrate anticancer efficacy against CRC.
Method(s): Eligible CRC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 3 prior lines of standard therapy for metastatic disease, including an anti-VEGF monoclonal antibody. Formalin-fixed paraffin-embedded tissue from an archival or a core tumor sample must be available for biomarker analysis. Samples will be tested using Oncomap ExTra with the Xerna TME Panel where patient samples will be classified into one of four tumor microenviroment (TME) subtypes based on angiogenic and immune gene expression signatures. Up to 30 patients will be enrolled to each CRC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort A1) or in combination with irinotecan (180 mg/m2 on Days 1 and 15 of a 28-day cycle, Cohort A2). Patients will have radiologic tumor assessments every 8 weeks and will continue to receive treatment until disease progression per RECIST v1.1 (as assessed by the investigator), unacceptable toxicity, withdrawal of consent, another protocol-defined discontinuation criterion is met, or the sponsor terminates the study, whichever occurs first. The primary endpoints of the study are objective response rate (ORR) and progression-free survival (PFS). The historical benchmarks for this patient population are estimated at an ORR of <5% and a 25% PFS rate at 4 months, with targets of 15% and 50% respectively considered promising for this study. Interim efficacy assessments will be at 10-patient increments following the time patients have had at least 1 post-baseline scan. Cohort continuation and future evaluation decisions will be guided by the boundaries identified by a sequential monitoring procedure. Secondary efficacy endpoints include overall survival, time to response, disease control rate, duration of response, and the relationship between antitumor activity of navicixizumab and Xerna TME Panel biomarker subtypes
Grain, Gluten, and Dietary Fiber Intake Influence Gut Microbial Diversity: Data from the Food and Microbiome Longitudinal Investigation
UNLABELLED:< 0.05). These findings suggest that whole grain and dietary fiber are associated with overall gut microbiome structure, largely fiber-fermenting microbiota. Higher refined grain and gluten intakes may be associated with lower microbial diversity. SIGNIFICANCE:Regular consumption of whole grains and dietary fiber was associated with greater abundance of gut bacteria that may lower risk of colorectal cancer. Further research on the association of refined grains and gluten with gut microbial composition is needed to understand their roles in health and disease.
Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies
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 (TRM), 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 TRM 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.
Corrigendum: Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies
[This corrects the article DOI: 10.3389/fimmu.2023.1067352.].
Phase II study of lenvatinib plus pembrolizumab for patients with immunotherapy-naive advanced gastric cancer following first line therapy [Meeting Abstract]