Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics

Abstract

Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy after progression to platinum-based therapy were prospectively studied. Samples from peripheral blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified by flow cytometry and correlated with HPD as identified with radiological criteria. A strong expansion of highly differentiated CD28− CD4 T lymphocytes (CD4 THD) between the first and second cycle of therapy was observed in HPD patients. After normalizing, the proportion of posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the rest of patients (median 1.525 vs. 0.990; p = 0.0007), and also when stratifying by HPD, non-HPD progressors, and responders (1.525, 1.000 and 0.9700 respectively; p = 0.0025). A cut-off value of 1.3 identified HPD with 82% specificity and 70% sensitivity. An increase of CD28− CD4 T lymphocytes ≥ 1.3 (CD4 THD burst) was significantly associated with HPD (p = 0.008). The tumor growth ratio (TGR) was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients (median 2.67 vs. 0.86, p = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03, p = 0.0126). A strong expansion of CD28− CD4 lymphocytes in peripheral blood within the first cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in clinical practice and complements radiological evaluation.

Emerging Blood-Based Biomarkers for Predicting Response to Checkpoint Immunotherapy in Non-Small-Cell Lung Cancer

“…Further analysis revealed that these highly differentiated CD4 + T cells were mainly composed of non-exhausted memory (CD45RA − CD62L +/− ) CD4 cells, which significantly affect T cell proliferation response during immunotherapy ( 47 ). Subsequently, this research team conducted a prospective study in 70 NSCLC patients treated with ICIs, indicating that HPD was closely associated with dysfunctional CD4 immunity and an increased number of peripheral CD28 − CD4 + T cells ( 48 ). Julia et al also highlighted the importance of functional CD4 T cell immunity for anti-tumor response, and they observed higher baseline proportion of central memory CD4 + T cells in responders ( 40 ).…”

Resistance to PD-L1/PD-1 Blockade Immunotherapy. A Tumor-Intrinsic or Tumor-Extrinsic Phenomenon?

“…In our particular NSCLC cohort, a low baseline percentage of memory CD27-CD28-CD4 T cells correlated with intrinsic resistance (Zuazo et al, 2019). Moreover, a sudden increase in highly differentiated CD4 T cells (CD4 T HD burst) following the first cycle of immunotherapy was indicative of hyperprogressive disease (Zuazo et al, 2018;Arasanz et al, 2020). The identification of hyperprogressors is also of the outmost importance, as these patients deteriorate very quickly with fatal outcomes.…”

Immunotherapy for Ovarian Cancer: Adjuvant, Combination, and Neoadjuvant

“…For ovarian cancer, retrospective analysis of data from a clinical trial with a cohort of 89 patients that received ICB showed that over half of the patients (N = 46, 51.6%) experienced early treatment discontinuation (≤12 weeks after treatment initiation) due to radiographic or clinical disease progression ( 122 ). The biological basis and mechanisms underlying HPD, such as the Fc region of antibodies ( 123 ), EGFR and MDM2/MDM4 amplification ( 123 ), and senescent CD4+ T cells ( 124 ), are being clarified. This phenomenon has polarized oncologists, who debate whether this effect could still reflect the natural history of the disease.…”