Faculty Bibliography

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

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

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.

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.].

The human oral microbiome is associated with chronic diseases including cancer. However, our understanding of its relationship with diet is limited. We assessed the associations between carbohydrate and glycemic index (GI) with oral microbiome composition in 834 non-diabetic subjects from the NCI-PLCO and ACS-CPSII cohorts. The oral microbiome was characterized using 16Sv3-4 rRNA-sequencing from oral mouthwash samples. Daily carbohydrate and GI were assessed from food frequency questionnaires. We used linear regression, permutational MANOVA, and negative binomial Generalized Linear Models (GLM) to test associations of diet with α- and β-diversity and taxon abundance (adjusting for age, sex, cohort, BMI, smoking, caloric intake, and alcohol). A q-value (FDR-adjusted P-value) of <0.05 was considered significant. Oral bacterial α-diversity trended higher in participants in the highest quintiles of carbohydrate intake, with marginally increased richness and Shannon diversity (p-trend=0.06 and 0.07). Greater carbohydrate intake was associated with greater abundance of class Fusobacteriia (q=0.02) and genus Leptotrichia (q=0.01) and with lesser abundance of an Actinomyces OTU (q=4.7E-04). Higher GI was significantly related to greater abundance of genus Gemella (q=0.001). This large, nationwide study provides evidence that diets high in carbohydrates and GI may influence the oral microbiome.

Background: Neoadjuvant chemoradiation (CRT) followed by surgical resection is a standard approach for patients (pts) with locally advanced esophageal/GEJ cancers. A pathologic complete response (pCR) is achieved in 22-23% of adenocarcinomas (AC) and 42-49% of squamous cell carcinomas (SCC) and is associated with improved survival outcomes. Sotigalimab (sotiga) is a high affinity, potent CD40 agonist mAb capable of inducing and expanding anti-tumor immune responses by activating dendritic cells (DCs), T cells, NK cells, B cells, and M1 macrophages. This study examined the safety and efficacy of combining sotiga with neoadjuvant CRT in pts with esophageal/GEJ cancers.
Method(s): Pts with resectable (T1-3, Nx) AC or SCC of the esophagus/GEJ were eligible. T1N0 and cervical tumors were excluded. Study treatment: carboplatin (AUC 2)/paclitaxel (PTX) (50 mg/m²) weekly x 5 with radiation 5040 cGy plus up to 4 doses of sotiga 0.3mg/kg IV prior to Ivor-Lewis esophagectomy. Primary efficacy endpoint was pCR.
Result(s): 34 pts were enrolled (safety pop). Histology: 76% AC, 24% SCC; clinical stage: II/III/IVA, 9%/68%/23%; location: GEJ 47%. AEs (> 20%) attributed to sotiga: nausea, chills, fatigue, cytokine release syndrome (CRS), pyrexia, vomiting, abnormal LFTs, thrombocytopenia, diarrhea, and pruritus; majority Grade 1-2. Grade >3 CRS was observed in 3 pts (9%). No pt withdrawals due to sotiga; no treatment-related deaths. 28 pts were evaluable for the primary endpoint (3 opted against surgery, 1 pt withdrew after PTX reaction, 1 unrelated death, 1 surgery still pending). Path responses: 10 pCR (36%), 16 pPR (57%), 18 major path resp (<10% residual tumor) (64%). 2 PD (7%), ORR 93%. pCR by histology: 7/23 AC (30%), 3/5 SC (60%). Post-tumor samples demonstrated increased infiltration and activation of DCs and monocytes compared to baseline.
Conclusion(s): Sotiga combined with neoadjuvant chemoradiation for esophageal/GEJ cancers was generally well tolerated and achieved pCR rates in both AC and SCC that compare favorably to historical data and are promising for this treatment strategy. Additional evaluations of clinical outcomes (including DFS, OS) and immune-based biomarkers are ongoing. Clinical trial identification: NCT03165994. Legal entity responsible for the study: Apexigen, Inc.
Funding(s): Apexigen, Inc. Disclosure: A.H. Ko: Financial Interests, Personal, Other, Member of Data Monitoring Committee: Imugene, Erytech, Roche/Genentech, Ipsen; Financial Interests, Personal, Other, Developed content for web-based platform as well as lecture materials on pancreatic cancer; speaker at multiple CME activities: Clinical Care Options; Financial Interests, Personal, Other, Member and now chair of Pancreatic Cancer Task Force: National Cancer Institute; Financial Interests, Institutional, Invited Speaker, Local PI for clinical trial (pancreatic cancer): Celgene, Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Local PI for clinical trial (esophageal cancer): Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, National PI for clinical trial (GI cancers): Abgenomics; Financial Interests, Institutional, Invited Speaker, National PI for clinical trial (esophageal cancer): Apexigen; Financial Interests, Institutional, Invited Speaker, Local PI for clinical trial (gastric cancer): Leap Therapeutics, Astellas; Non-Financial Interests, Other, MemberMultiple prior committee/speaking roles for Annual MeetingAssociate Editor: American Society of Clinical Oncology; Non-Financial Interests, Sponsor/Funding, For Precision Promise clinical trials consortium. Funding paid directly to my institution.: Pancreatic Cancer Action Network; Non-Financial Interests, Sponsor/Funding, For clinical trials collaboration. Funding paid directly to my institution.: Parker Institute for Cancer Immunotherapy. M. Noel: Financial Interests, Personal, Advisory Role: Celgene, Taiho Pharma, Ipsen; Financial Interests, Personal, Speaker's Bureau: Celgene, Taiho Pharma, Daiichi Sankyo/ AstraZeneca; Financial Interests, Institutional, Funding: Apexigen. J. Chao: Financial Interests, Personal, Advisory Role: Lilly, Merck, AstraZeneca, Daiichi Sankyo, Ono Pharma, Bristol Myers Squibb, Astellas Pharma, Turning Point Thera, Roche, Silverback Thera, Novartis, Coherus Biosciences, Geneos; Financial Interests, Personal, Advisory Role, +travel: Foundation Medicine, Macrogenics, Amgen; Financial Interests, Personal, Speaker's Bureau, +travel: Merck; Financial Interests, Personal, Speaker's Bureau: Bristol Myers Squibb; Financial Interests, Institutional, Funding: Merck, Novonco Thera, Brooklyn Immunotherapeutics, Apexigen. D. Sohal: Financial Interests, Personal, Advisory Role: Perthera, Ability Pharma, AstraZeneca; Financial Interests, Personal, Speaker's Bureau: Incyte, Genentech; Financial Interests, Personal, Other, Honoraria: Foundation Medicine; Financial Interests, Institutional, Funding: Celgene, Genentech, Bristol-Myers Squibb, Incyte, Rafael Pharma, Apexigen, Amgen, Ability Pharma, AstraZeneca, FibroGen, Merck. M. Crow: Financial Interests, Personal, Funding: Merck, Incyte, Janssen; Financial Interests, Institutional, Funding: Apexigen. P.E. Oberstein: Financial Interests, Personal, Advisory Role, +travel: Merck; Financial Interests, Personal, Advisory Role: Rubius Thera, QED Thera, AstraZeneca, Delcath Systems; Financial Interests, Personal, Speaker's Bureau: AstraZeneca; Financial Interests, Personal, Expert Testimony: Ipsen; Financial Interests, Institutional, Funding: Merck, Roche/Genentech, Rafael Pharma, Arcus BioSciences. A. Scott: Financial Interests, Personal, Advisory Role, +travel: Exelixis, QED Pharma; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Stocks/Shares: Johnson johnson; Financial Interests, Personal, Funding: Exelixis, Genentech, Incyte, Five Prime, Merck; Financial Interests, Institutional, Funding: Apexigen. A. McRee: Financial Interests, Personal, Full or part-time Employment, recent move to industry: Janssen; Financial Interests, Personal, Stocks/Shares: Johnson Johnson; Financial Interests, Institutional, Funding: Inovio Pharma, Novartis, Merck, Boston Biomedical, AstraZeneca, Rgenix, BioMed Valley Discoveries, Takeda. C. Rocha Lima: Financial Interests, Personal, Funding: Rafael Pharma, Boston Biomedical, Pharmacyclics; Financial Interests, Institutional, Funding: Apexigen. L. Fong: Financial Interests, Personal, Stocks/Shares: Actym, Allector, Atreca, Bioatla, Bolt, Immunogenesis, Nutcracker, RAPT, Scribe, Senti, Soteria, TeneoBio; Financial Interests, Personal, Ownership Interest: Keyhole; Financial Interests, Institutional, Funding: Abbvie, Bavarian Nordic, Dendreon, Janssen, Merck, Roche/Genentech; Financial Interests, Personal and Institutional, Funding: BMS; Financial Interests, Institutional, Invited Speaker: Corvus; Financial Interests, Personal, Funding: AstraZeneca, Merck KGA. B. Keenan: Financial Interests, Institutional, Funding: Partner Therapeutics. E. Filbert: Financial Interests, Personal, Full or part-time Employment: Apexigen; Financial Interests, Personal, Stocks/Shares: Apexigen. F.J. Hsu: Financial Interests, Personal, Full or part-time Employment: Apexigen; Financial Interests, Personal, Officer: Apexigen. V. Shankaran: Financial Interests, Personal, Other, Honoraria: Cambia Health Foundatio; Financial Interests, Institutional, Funding: Amgen, Merck, Bayer, Bristol Myer Squibb, AstraZeneca, Genentech/Roche, Apexigen.
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BACKGROUND:Genetic testing is recommended for all pancreatic ductal adenocarcinoma (PDAC) patients. Prior research demonstrates that multidisciplinary pancreatic cancer clinics (MDPCs) improve treatment- and survival-related outcomes for PDAC patients. However, limited information exists regarding the utility of integrated genetics in the MDPC setting. We hypothesized that incorporating genetics in an MDPC serving both PDAC patients and high-risk individuals (HRI) could: (1) improve compliance with guideline-based genetic testing for PDAC patients, and (2) optimize HRI identification and PDAC surveillance participation to improve early detection and survival. METHODS:Demographics, genetic testing results, and pedigrees were reviewed for PDAC patients and HRI at one institution over 45 months. Genetic testing analyzed 16 PDAC-associated genes at minimum. RESULTS:Overall, 969 MDPC subjects were evaluated during the study period; another 56 PDAC patients were seen outside the MDPC. Among 425 MDPC PDAC patients, 333 (78.4%) completed genetic testing; 29 (8.7%) carried a PDAC-related pathogenic germline variant (PGV). Additionally, 32 (9.6%) met familial pancreatic cancer (FPC) criteria. These PDAC patients had 191 relatives eligible for surveillance or genetic testing. Only 2/56 (3.6%) non-MDPC PDAC patients completed genetic testing (p < 0.01). Among 544 HRI, 253 (46.5%) had a known PGV or a designation of FPC, and were eligible for surveillance at baseline; of the remainder, 15/291 (5.2%) were eligible following genetic testing and PGV identification. CONCLUSION/CONCLUSIONS:Integrating genetics into the multidisciplinary setting significantly improved genetic testing compliance by reducing logistical barriers for PDAC patients, and clarified cancer risks for their relatives while conserving clinical resources. Overall, we identified 206 individuals newly eligible for surveillance or genetic testing (191 relatives of MDPC PDAC patients, and 15 HRI from this cohort), enabling continuity of care for PDAC patients and at-risk relatives in one clinic.

Background: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy that is refractory to therapeutic targeting of the immune microenvironment. In preclinical work, IL-1beta was shown to be upregulated in pancreatic cancer tumors, and in mouse models, IL-1beta expression led to activation of pancreatic stellate cells and immunosuppression (Das et al 2020). We hypothesize that blockade of IL-1beta and PD-1 will result in alterations in myeloid, lymphoid, and fibroblast subsets within the pancreatic cancer microenvironment and add therapeutic benefit in combination with chemotherapy in PDA.
Method(s): We are conducting an open-label multicenter Phase Ib study evaluating a 4 drug regimen including gemcitabine and nabpaclitaxel with the addition of canakinumab (ACZ885), a high-affinity human anti-interleukin1beta (IL-1beta) monoclonal antibody (mAb), and spartalizumab (PDR001), a mAb directed against human Programmed Death-1 (PD-1). Eligible subjects have metastatic PDA without prior anticancer therapy for metastatic disease and RECIST measurable disease. The primary objective was to identify a recommended phase II/III dose of combination therapy by evaluating the incidence of dose limiting toxicities in the first 56 days (8 weeks) of dosing in at least 6 evaluable subjects utilizing a Bayesian logistic regression model. All subjects underwent baseline and on-study tissue and blood collection for extensive exploratory correlative studies. Secondary objectives including safety and tolerability of quadruple therapy and preliminary assessment of clinical activity.
Result(s): 10 subjects were enrolled between November 2020 and March 2021, and the first 6 subjects to complete 8 weeks of therapy were included in the dose confirmation analysis. There were no dose limiting toxicities and the recommended Phase II/III dose was established as; gemcitabine (1000 mg/m2 IV) on day 1,8,15; nab-paclitaxel (125 mg/m2 IV) on day 1,8,15, canakinumab (250 mg via subcutaneous injection) on day 1, spartalizumab (400 mg IV) on day 1; of each 28 day cycle. Adverse events were consistent with those seen with chemotherapy and were predominately hematologic. The majority of subjects completed the on-treatment blood and tissue collection for correlative analysis. The study is ongoing with subjects remaining on therapy and all subjects will be evaluated for efficacy.
Conclusion(s): In this Phase Ib study, we demonstrated the feasibility and safety of adding canakinumab and spartalizumab to standard of care chemotherapy in first line metastatic PDA and established the recommended Phase II/III dose. This novel 4 drug combination will be tested in a randomized Phase II/III study through the Precision Promise clinical trial network. Preliminary correlative and efficacy data will be reported