Natural Killer T cell lymphoma (NKTL) is a highly aggressive form of cancer more frequently occurring in Asia than other parts of the world with very poor treatment outcomes in the advanced stages. Currently, there is still no clear consensus on primary therapy, and chemoradiation or L-Asparaginase therapy remain mainstay treatments. Hence, novel and effective treatment strategies are needed.

Daratumumab is a monoclonal antibody that is utilised in cancer treatment to specifically target the CD38 protein on malignant cells. It is designed to work with various partners in your immune system to achieve a long-term immune-mediated response against cancer. Compared with chemotherapy drugs, monoclonal antibody treatments tend to have less serious side effects.

Here, a group of researchers from the Cancer Science Institute of Singapore (CSI Singapore), NUS and Janssen Pharmaceuticals has identified a subgroup of NKTL patients expressing high levels of CD38 proteins who may benefit from daratumumab treatment. This is further supported by parallel phase 2 clinical trials performed by other colleagues in the field, which have demonstrated that utilising daratumumab monotherapy as a novel treatment option in NKTL patients was safe, well tolerated and exhibited an encouraging response.

The research team has also presented a more nuanced understanding of the efficacy of daratumumab treatment response. They have established that treatment efficacy is not only dependent on the expression levels of target protein CD38, but more critically on the ratio of CD38 with another group of proteins present on the cancer cell surface called complement inhibitory proteins (CIPs). CIPs inhibit the recruitment and activation of immune co-factors which mediate complement-dependentcytotoxicity (CDC), an essential component of anti-cancer response activated by daratumumab.

Rational treatment strategies which increase the CD38:CIP ratio in patients can thus potentially enhance the therapeutic response to daratumumab. Preclinical studies by the scientists have identified All-trans retinoic acid (ATRA), which has been successfully applied in the clinical treatment of APL patients, as a promising candidate  for enhancing CD38:CIP ratio and consequently potential treatment outcomes in NKTL patients when combined with daratumumab

This study also highlights the utilization of the CD38:CIP ratio as a far more robust identifier for patient stratification to treatment response, as compared to CD38 expression levels alone. Our findings propose a novel rational approach for the clinical evaluation and optimization of daratumumab response in future clinical trials, particularly with strategies that can improve the CD38: CIP ratio in patients. “Immune-response based strategies against cancer often offer a long term and sustainable treatment response and it is exciting that this can be potentially extended to NKTL patients who often face an aggressive disease. Importantly, identifying safe treatment combinations which can enhance the CD38: complement inhibitory protein (CIP) determinant in patients will be important in optimizing patient responses. This concept applies not only to daratumumab but can be extended to other monoclonal antibody-based therapies which activate similar immune-mediate anti-cancer responses,” explained Dr. Nurulhuda Binte Mustafa, Senior Research Fellow from CSI Singapore.

Professor Chng Wee Joo, Deputy Director and Senior Principal Investigator at CSI Singapore, who led the study, added, “Results of our study will allow better optimization of treatment with Daratumumab to more effectively utilize this exciting therapy for NK/T lymphoma.”

The study was published in scientific journal, Journal for ImmunoTherapy of Cancer, in July 2021.

Read more on the study here.