Hyperprogressive Disease After Combined Anti-PD-L1 and Anti-CTLA-4 Immunotherapy for MSI-H/dMMR Gastric Cancer: A Case Report

Abstract

Immune checkpoint inhibitors (ICI) have been developed in gastric adenocarcinomas and approved in first-line metastatic setting (in combination with chemotherapy) as well as in pretreated patients. Microsatellite instability-high (MSI-H) tumors are predicted to derive high benefit from ICI but data in gastric locations are limited. Here, we describe the case of a 68-year old patient with stage IV MSI-H gastric adenocarcinoma, referred to our center to receive immunotherapy after failure of standard of care (surgery with perioperative platin-based chemotherapy and paclitaxel plus ramucirumab at disease progression). The patient received one injection of durvalumab and tremelimumab and was hospitalized eighteen days after because of occlusive syndrome. The CT scan showed hyperprogression of the lymph nodes and hepatic lesions, compressing the gastric stump. He died few days later. Molecular analyses did not explain this outcome. To our knowledge, this is one of the first reported cases of hyperprogressive disease after combined ICI for a patient with MSI-H tumor. We review the potential causes and discuss the emerging literature regarding predictive factors of hyperprogression in the particular subset of MSI-H patients. If some data were available in retrospective studies, validation of strong predictive factors is needed to avoid such dramatic evolutions.

Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti–PD-1 immunotherapy

“…This work is consistent with previous findings that have implicated various myeloid cell populations as playing a critical role in promoting metastatic disease progression, and it also highlights HSP70 as a previously undescribed soluble factor released by tumors that systemically drive PMN-MDSC accumulation (21). This relationship between circulating PMN-MDSCs or neutrophils and HPD has been described in previous studies, although the underlying mechanisms linking these phenomena have not been elucidated (44). Just as we have shown HSP70 to signal through TLR4 to up-regulate Wnt5a signaling through an autocrine tumor-intrinsic mechanism in a prior study, this current work shows that circulating HSP70 induces the TLR4-Wnt5a-CXCL5/ G-CSF signaling cascade in distant lung epithelial cells (19).…”

Signaling pathways and therapeutic interventions in gastric cancer

“…A recent case report showed hyperprogression of the lymph nodes and liver lesions compressing the gastric stump from a 68-year-old patient with stage IV MSI subtype GC after receiving immunotherapy of durvalumab (PD-1 inhibitor) and tremelimumab (CTLA-4 inhibitor). 421 More study is still needed to evaluate the therapeutic significance of CTLA-4 in GC.…”