: Immune checkpoint inhibitors (ICIs) are immunomodulatory antibodies that intensify the host immune response, thereby leading to cytotoxicity. The primary targets for checkpoint inhibition have included cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death receptor-1 (PD-1) or programmed cell death ligand-1 (PD-L1). ICIs have resulted in a change in treatment landscape of various neoplasms. Among hematologic malignancies, ICIs have been most successful in certain subtypes of lymphomas such as classic Hodgkin lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBCL). However, there have been several challenges in harnessing the host immune system through ICI use in other lymphomas. The underlying reasons for the low efficacy of ICI monotherapy in most lymphomas may include defects in antigen presentation, non-inflamed tumor microenvironment (TME), immunosuppressive metabolites, genetic factors, and an overall lack of predictive biomarkers of response. In this review, we outline the existing and ongoing studies utilizing ICI therapy in various lymphomas. We also describe the challenges leading to the lack of efficacy with ICI use and discuss potential strategies to overcome those challenges including: chimeric antigen receptor T-cell therapy (CAR-T therapy), bispecific T-cell therapy (BiTE), lymphocyte activation gene-3 (LAG-3) inhibitors, T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) inhibitors, vaccines, promotion of inflammatory macrophages, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi). Tumor mutational burden and interferon-gamma release assays are potential biomarkers of ICI treatment response beyond PD-L1 expression. Further collaborations between clinicians and scientists are vital to understand the immunopathology in ICI therapy in order to improve clinical outcomes.
e16311 Background: Patients with mutations in BRCA 1/2 genes are at increased risk for pancreatic ductal cell adenocarcinoma (PDAC) in addition to breast and ovarian cancer. In 2019, the NCCN updated its guidelines recommending gene testing for all patients with PDAC to include associated genes: ATM, BRCA1, BRCA2, CDKN2A, MSH2, MLH1, MSH6, EPCAM, PALB2, STK11, TP53. This retrospective, observational study reports on adherence to genetic screening recommendations among patients with newly diagnosed PDAC who received oncologic care in rural Northeast Georgia (NEGA). Methods: Chart abstraction was performed utilizing the EPIC database from hospital electronic medical records of patients who were diagnosed with PDAC between 1/1/20-12/31/21 and received oncologic care in rural NE GA. This abstraction was completed to include information on gene testing recommendations, testing completion, and time from diagnosis to testing. The deidentified dataset was then analyzed using appropriate descriptive and associative statistical testing. Results: Of the cohort of 109 patients diagnosed with PDAC over these two years, only 32 (29.4%) received recommendations and completed genetic screening. Among this segment of patients, 16 (14.7%) were screened within 10 days of diagnosis, 8 (7.3%) within 11-30 days, and 6 (5.5%) were screened over 30 days after being diagnosed with PDAC. Among the 77 (70.6%) patients who did not receive screening, 45 of them (41.3%) did not receive any discussion regarding screening despite planning for other standard of care treatment. The remaining 32 patients (29.4% of the no screening cohort) did not receive screening due to desire to pursue palliative care/hospice/or due to terminal illness that prevented further workup. Of the 45 patients who did not receive screening despite PDAC treatment intent, majority (43; 95.5%) did not receive recommendations regarding the importance of genetic screening. Gene testing of the 32 patients who had screening completed showed that 4 (12.5%) had a pathogenic mutation (3 with CFTR; 1 ATM) and 16 (50%) had variants of unknown significance (VUS). Conclusions: This study highlights a gap in adherence to guideline-directed genetic testing in PDAC patients. Notable findings include increased likelihood to complete the test when recommendations and discussions of genetic screening occurred early in the course after initial diagnosis of PDAC. Moreover, 12.5% of those screened were found to have pathogenic mutation and half were found to have at least one VUS suggesting that genetic screening may potentially identify causative mutations. The findings also highlight the consideration for gene testing recommendation for the large proportion of patients who are terminally ill at diagnosis, as genetic screening would potentially benefit the family members and inform that they receive genetic screening as well.
