PD-1 inhibition in patient derived tissue cultures of human gastric and gastroesophageal adenocarcinoma

Abstract

Emerging immunotherapies quest for better patient stratification in cancer treatment decisions. Moderate response rates of PD-1 inhibition in gastric and esophagogastric junction cancers urge for meaningful human model systems that allow for investigating immune responses ex vivo . Here, the standardized patient-derived tissue culture (PDTC) model was applied to investigate tumor response to the PD-1 inhibitor Nivolumab and the CD3/CD28 t-lymphocyte activator ImmunoCult TM . Resident t-lymphocytes, tumor proliferation and apoptosis, as well as bulk gene expression data were analyzed after 72 h of PD-1 inhibition either as monotherapy or combined with Oxaliplatin or ImmunoCult TM . Individual responses to PD-1 inhibition were found ex vivo and combination with chemotherapy or t-lymphocyte activation led to enhanced antitumoral effects in PDTCs. T-lymphocyte activation as well as the addition of pre-cultured peripheral blood mononuclear cells improved PDTC for studying t-lymphocyte and tumor cell communication. These data support the potential of PDTC to investigate immunotherapy ex vivo in gastric and esophagogastric junction cancer.

3D tumor explant as a novel platform to investigate therapeutic pathways and predictive biomarkers in cancer patients

“…Our data suggest that ex vivo ICI treatment of PDE simulates an active antitumor immune response, thereby providing a proof-of-concept strategy to identify patients who might benefit from such kind of treatment. Our results are in line with the numerous other investigators operating in the 3D cancer model field (15,17,20,22,24,25) and we encourage the establishment in the clinics of personalized ex vivo platforms to test immunotherapy efficacy, define prediction markers and develop combination strategies. We underline that preclinical or co-clinical testing of immunotherapeutic agents must rely on 3D models, such as PDO (59), PDOTS (17) or PDTF (22), representing the most accurate patient-tailored TME replicas.…”

“…In this setting, the secretion of cyto/chemokines, along with T cell activation levels measured in a PDE model of patient-derived tumor fragments (PDTF) from different tumor types embedded into an artificial extracellular matrix, could predict clinical response to PD-1 blockade ( 22 ). Similar observations were recorded following PD-1 inhibition in explant cultures of head and neck cancer, gastric and gastroesophageal adenocarcinoma ( 23 , 24 ). Importantly, the PDTF platform can be also applied to identify suitable neoadjuvant treatment strategies in patients with early-stage cancer, as recently described for anti-CTLA-4 plus anti-PD-1 combined with IL-2 in PDE of checkpoint inhibitor-resistant melanoma patients ( 25 ).…”

Analysis of polymeric nanoparticle properties for siRNA/DNA delivery in a tumor xenograft tissue slice air–liquid interface model

“…Thus, the immunomodulatory effects of nanoparticles will require tissue material from an immunocompetent background. However, in these tissues, immune cells, such as T lymphocytes, can retain their viability in ALI tissue slice culture for several days, [ 26 ] which is sufficient for assessing nanoparticle effects. Similarly, (cyto‐)toxic effects can also be monitored.…”

PD-1 blockade synergizes with oxaliplatin-based, but not cisplatin-based, chemotherapy of gastric cancer

“… 25 However, in many cases ICI monotherapy fails to confer sufficient benefit due to the lack of pre-existing immune priming. 26–28 Therefore, ICD-inducing regimens that are capable of stimulating adaptive anticancer immunity appear as particularly promising combinations for generating synergistic effects with ICIs. The concept of combining immunogenic chemotherapies with ICIs is supported by several preclinical studies generally employing ICD inducers to prime an adaptive antitumor immune response several days or weeks before the administration of ICIs ( Table 1 ).…”