Novel combination therapy shows promise for aggressive lymphoma resistant to immunotherapy

A study published in Cancer Discovery finds that combining an epigenetic therapy with an anti-PD-1 antibody, which uses the body’s natural response to viral infections, shows promising results in patients with relapsed or refractory natural killer/T-cell lymphoma (R/R NKTL), a rare and aggressive cancer with limited treatment options.

Authors of the study include Jing Tan, Ph.D., and Huiqiang Huang, MD, principal investigators in the State Key Laboratory of Oncology in South China at the Sun Yat-sen University Cancer Center, and Choon Kiat Ong, Ph.D., principal investigator in the Lymphoma Translational Research Laboratory at the Division of Cellular and Molecular Research at the National Cancer Center Singapore.

“R/R NKTL is a rare subtype of non-Hodgkin lymphoma that currently has no standard treatment strategy,” said Tan.

Anti-PD-1 therapy, which involves helping the immune system to better find and attack the cancer cells, has shown promise for R/R NKTL treatment, but many patients either do not respond or develop resistance, he explained.

DNA methyltransferase (DNMT) inhibitors are epigenetic modifying enzyme drugs that can activate silenced genes called endogenous retroviral elements, according to Ong.

Endogenous retroviral elements are remnants of ancient viral infections now embedded in the human genome, and when activated, put the body’s immune system into high alert, a process called “viral mimicry,” he explained.

“We hypothesized that DNMT inhibitors could trigger viral mimicry and change a ‘cold’ tumor ‘hot,’ thereby restoring NKTL sensitivity to anti-PD-1 therapy,” said Ong.

Tan and collaborators conducted a retrospective analysis of 21 patients with R/R NKTL who initially responded to anti-PD-1 therapy but subsequently experienced disease recurrence. The researchers treated these patients with a combination of the PD-1 inhibitor sintilimab and either decitabine or azacitidine, both DNMT inhibitors. Preclinical mouse models were also developed to study mechanisms of resistance and response.

Of the 21 patients, 10 had complete remission and four had a partial response following treatment with the combination. The two-year overall survival rate was 50.2%. Preclinical data showed that DNMT inhibitors reversed immune resistance by demethylating (activating) endogenous retroviral elements.

Tan and collaborators showed that this activation caused an immune response through a specific mechanism called the type 1 interferon signaling pathway, attracting the CD8-positive T cells into the tumor, making it vulnerable to attack.

“This new therapy achieves a significantly improved median OS, compared to the three-month benchmark for patients whose disease has progressed after anti-PD-1 treatment, and this combination therapy can potentially be curative for a subset of patients who experience recurrence,” said Huang.

“Our study highlights the utility of DNMT inhibitors in switching on the immune response through viral mimicry,” said Huang. “This combination therapy offers a scientifically validated and immediately accessible option that could significantly improve survival for patients with R/R NKTL,” he added.

This finding is consistent with previous studies on other cancer types suggesting that viral mimicry response presents a promising strategy to enhance the effectiveness of immunotherapy delivered to tumors, noted Tan.

A limitation of this study is its retrospective nature and small sample size, which may introduce selection bias, limiting the applicability of this study’s findings to a wider population. Another limitation is the rarity of NKTL and the retrospective design constraining the researchers’ ability to obtain sufficient tumor tissue for comprehensive profiling and analysis.

Further, although the preclinical model used in the study demonstrated that the acquired resistance to anti-PD-1 treatment was associated with the typical features of “cold” tumors, the exact tumor microenvironment characteristics in NKTL patients were not investigated in this study.