825O - Genomic traits of therapeutic response to anti-PD-1 therapy in peripheral T cell lymphoma

Background

The use of immune checkpoint inhibitors has revolutionized the treatment of solid tumors and hematologic malignancies, clinical evidence has demonstrated anti-PD-1 therapy to be effective tools in PTCL. However, factors that may influence primary sensitivity or resistance to anti-PD-1 therapy in PTCL, such as TMB and genomic alterations, have not yet been clarified.

Methods

We enrolled 89 peripheral T cell lymphoma (PTCL) patients in phase II clinical trial of geptanolimab and performed targeted next-generation sequencing for 440 cancer-associated genes. Clinical data were collected and correlated with genetic mutations. In vitro, studies were conducted to evaluate the effect of JAK3 mutations on PD-L1 expression.

Results

PD-L1 expression was significantly elevated in complete response (CR)/ partial response (PR) patients compared to progressive disease (PD) patients, while tumor mutation burden (TMB) didn’t exhibit significant prognostic value which may be confounded by the variation across PTCL subtypes. The most frequent mutations occurred in TP53, KMT2C, KMT2D, JA3, LRP1B, and SETD2. Shorter time to death was related to mutations in SETD2 (HR=5.73, P=0.0135) or KME2D (HR=3.17, P=0.0533). Shorter PFS was correlated with JAK3 mutations (HR=5.97, P=0.0144). The subset PTCL patients (86.4%) with enrichment of non-APOBEC-related mutation signature had higher TMB level (P=0.076) and superior PFS (P=0.031) to non-APOBEC-enriched samples. In vitro experiments revealed JAK3 A573V, M511I, and E958K mutations led to lower PD-L1 expression through downregulated of the expression of PI3K and MAPK.

Conclusions

In this study we comprehensively depicted the pre-treatment mutation profiles of PTCL and identified genetic alterations with prognostic value for anti-PD-1 therapy. Notably, we found JAK3 mutations which are vital and prevalent in PTCL reduced PD-L1 levels in vivo and in vitro, which are of great clinical and biological sense.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.