Germline Signature Predicts Adverse Effects With Anti-PD1/PDL1 Checkpoint Therapy

Investigators have identified a germline biomarker signature that successfully predicts which patients will suffer serious adverse effects (AEs) when receiving anti-programmed cell death protein 1 (PD1) and programmed death-ligand 1 (PD-L1) therapy, according to a study published in the Journal for Immunotherapy of Cancer.

Checkpoint inhibitors that strengthen the immune system against PD-1 and PD-L1 are a promising new approach to cancer treatments, with research showing that they substantially improve the prognosis for patients with several advanced cancers. Potential treatment targets include melanoma, renal cell carcinoma, non-small cell lung cancer, Hodgkin lymphoma, and head and neck cancer, according to the study.

Despite their promise in cancer treatment, anti-PD1/PD-L1 therapies are also associated with a unique set of adverse effects, called immune-related AEs (irAEs). These effects are believed to be the result of an immune system overstimulated by the therapy, and although generally treatable, irAEs can be very serious and even fatal, according to the study.

Furthermore, there is also no way to predict which patients will develop irAEs before starting treatment, requiring clinicians to carefully observe patients closely in order to catch any symptoms. Notably, the toxicity from checkpoint therapy does not appear to be associated with a patient’s cancer or their response to the treatment, suggesting that it is a patient-specific reaction, according to the study.

Investigators identified a growing need to be able to predict which patients will experience irAEs. To address this knowledge gap, a team examined DNA signatures in 99 patients, looking for patterns that could indicate whether inherited biomarkers would predict toxicity. The researchers said they were able to identify a biomarker panel that predicts toxicity with 80% accuracy.

“These findings represent an important step toward personalizing checkpoint therapy, the use of which is growing rapidly,” said lead investigator Joanne B. Weidhaas, MD, PhD, MSM, in a press release. “While we are still at the early stages of understanding the mechanisms by which these germline mutations regulate immunity and the systemic stress response, our repeated findings that these variant panels can predict system toxic responses to cancer therapy are potentially paradigm-shifting.”

Applying these findings in practice could improve clinicians’ ability to offer truly personalized cancer therapy by enabling consideration of toxicity along with other data predicting patients’ response to treatment.

“As the efficacy of cancer therapy improves, resulting in higher and higher rates of long-term cancer control, cure without harm will only become an increasingly important endpoint,” the authors wrote in the press release.

REFERENCE

UCLA Jonsson Comprehensive Cancer Center scientists identify germline signature that predicts side effects from anti-PD1/PDL1 checkpoint therapy. News release. UCLA Health; February 3, 2022. Accessed February 4, 2022. https://www.uclahealth.org/news/WeidhaasGermline2022