Antibody–Fc/FcR Interaction on Macrophages as a Mechanism for Hyperprogressive Disease in Non–small Cell Lung Cancer Subsequent to PD-1/PD-L1 Blockade

Abstract

Hyperprogression (HP), a paradoxical boost in tumor growth, was described in a subset of patients treated with immune checkpoint inhibitors (ICI). Neither clinicopathologic features nor biological mechanisms associated with HP have been identified. Among 187 patients with non-small cell lung cancer (NSCLC) treated with ICI at our institute, cases with HP were identified according to clinical and radiologic criteria. Baseline histologic samples from patients treated with ICI were evaluated by IHC for myeloid and lymphoid markers. T-cell-deficient mice, injected with human lung cancer cells and patient-derived xenografts (PDX) belonging to specific mutational subsets, were assessed for tumor growth after treatment with antibodies against mouse and human programmed death receptor-1 (PD-1). The immune microenvironment was evaluated by flow cytometry and IHC. Among 187 patients, 152 were evaluable for clinical response. We identified four categories: 32 cases were defined as responders (21%), 42 patients with stable disease (27.7%), 39 cases were defined as progressors (25.7%), and 39 patients with HP (25.7%). Pretreatment tissue samples from all patients with HP showed tumor infiltration by M2-like CD163CD33PD-L1 clustered epithelioid macrophages. Enrichment by tumor-associated macrophages (TAM) was observed, even in tumor nodules from immunodeficient mice injected with human lung cancer cells and with PDXs. In these models, tumor growth was enhanced by treatment with anti-PD-1 but not anti-PD-1 F(ab) fragments. These results suggest a crucial role of TAM reprogramming, upon Fc receptor engagement by ICI, eventually inducing HP and provide clues on a distinctive immunophenotype potentially able to predict HP.

Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

“…In summary, despite the numerous research teams that have documented HPD , the existence of this phenomenon remains a matter of dispute. Indeed, an analysis of the OAK trial , which was a randomized study of checkpoint blockade versus chemotherapy in lung cancer, did not show a difference in the number of “fast progressors” between the arms.…”

“…It is important to note, however, that using pre‐immunotherapy imaging may not always be feasible for all treatment settings; for example, in the first‐line setting not all cancer patients have pre‐immunotherapy scans available. Therefore, some groups (Table ) have suggested criteria for HPD that do not require pre‐ immunotherapy scans; these criteria will need to be validated in patients with existing pre‐immunotherapy scans. Recent data have shown that HPD can be recapitulated in preclinical models .…”

“…Therefore, some groups (Table ) have suggested criteria for HPD that do not require pre‐ immunotherapy scans; these criteria will need to be validated in patients with existing pre‐immunotherapy scans. Recent data have shown that HPD can be recapitulated in preclinical models . As physicians make immunotherapy a mainstay of treatment in more cancer types, it will be imperative to develop predictive markers for HPD and to understand the biology that underlies this devastating irAE.…”

Hyperprogression after one dose of nivolumab in sinonasal cancer: A case report

“…One study has shown that MDM2 family amplification and epidermal growth factor receptor mutation may be associated with hyperprogression and poor clinical outcome . However, another study did not find any significant association in MDM2/4 amplification but argued that checkpoint inhibitors trigger Fc receptor in clustered epithelioid macrophages, leading to functional reprogramming toward a pro‐tumorigenic state leading to hyperprogression …”

“…9 However, another study did not find any significant association in MDM2/4 amplification but argued that checkpoint inhibitors trigger Fc receptor in clustered epithelioid macrophages, leading to functional reprogramming toward a pro-tumorigenic state leading to hyperprogression. 10 Literature on hyperprogression in HNSCC remains limited. In a retrospective study with 34 patients with recurrent and/or metastatic HNSCC, 29% of patients experienced hyperprogression based on a tumor growth kinetics ratio ≥2 based on pre-and postimmunotherapy imaging.…”