In the era of immunotherapy, where will the treatment of cancer patients go?

丨Author: Wang Liang 丨Unit: Lymphoma Diagnosis and Treatment Center, Department of Hematology, Beijing Tongren Hospital, Capital Medical University

Aunt Zhang, 65 years old, was diagnosed with "extranodal NK/T-cell lymphoma (stage IV)" in 2018 due to "nasal congestion for 5 years and multiple skin ulcers all over the body for 1 year". Stage IV means the tumor is in the late stage and the prognosis is often poor.

Aunt Zhang achieved temporary complete remission after six cycles of chemotherapy with the P-GEMOX regimen (pegaspargase + gemcitabine + oxaliplatin), but relapsed only half a year later, accompanied by recurrent high fever. According to our previous experience, if no new treatment options emerge, her survival may not exceed half a year.

Extranodal NK/T cell lymphoma, like the one Aunt Zhang suffers from, is a malignant lymphoma closely related to Epstein-Barr virus infection. It is common in East Asia and South America, but rare in Europe and the United States. my country has the highest number of extranodal NK/T cell lymphomas in the world, with more than 6,000 new patients each year. Nearly 80% of extranodal NK/T cell lymphomas occur in the upper respiratory tract, such as the nasal cavity, nasopharynx, and oropharynx, and most of them are early patients. Currently, the recommended treatment for early patients is combined chemotherapy (based on pegaspargase) on the basis of radiotherapy, with a cure rate of up to 80%. However, for patients with extranodal NK/T cell lymphoma that is not in the upper respiratory tract, advanced, relapsed, or refractory, the prognosis is extremely bleak, with an overall survival of less than 2 years.

The timely emergence of immunotherapy has brought new hope for such patients.

Aunt Zhang is undoubtedly lucky. When her disease relapsed, she encountered a new treatment plan - CHOPL (cyclophosphamide, vindesine + doxorubicin + prednisone + pegaspargase) combined with PD-1 monoclonal antibody (a new type of immunotherapy), and her condition was completely relieved again.

To avoid local recurrence, Aunt Zhang subsequently received PD-1 monoclonal antibody concurrent radiotherapy (consolidation radiotherapy was performed on the nasal lesions). Given that the patient was in the advanced stage and had a history of recurrence, in order to maximize the time of disease remission, we continued to give PD-1 monoclonal antibody maintenance therapy after radiotherapy. Currently, Aunt Zhang has been disease-free for more than 2 years. From this successful case, you can see that PD-1 monoclonal antibody played an important role in Aunt Zhang's condition.

So, what exactly is immunotherapy?

What impact will the emergence of immunotherapy have on the treatment of extranodal NK/T cell lymphoma?

Since immunotherapy was named one of the top ten scientific breakthroughs of the year by Science magazine in 2013, immunotherapy targeting PD-1/PD-L1 has sprung up in various lines of treatment for patients with various cancers. To date, more than 2,000 clinical studies around the world are actively exploring the best population, best timing of medication, and best combination for cancer immunotherapy.

In terms of mechanism of action, immunotherapy targeting PD-1/PD-L1 uses the body's own immune system to attack cancer by blocking the PD-1/PD-L1 signaling pathway, thereby relieving its inhibitory effect on T cells and promoting its killing effect on cancer cells. In other words, it is like cancer cells have lost their amulets, or T cells have been released from their brakes, causing cancer cells to die from the immune attack of T cells.

In 2016, our research team revealed the molecular mechanism by which Epstein-Barr virus induces extranodal NK/T cell lymphoma to express PD-L1, laying a theoretical foundation for the application of immunotherapy [1]. In 2019, the first prospective clinical trial in China, ORIENT-4, published data showing that sintilimab (PD-1 monoclonal antibody) monotherapy for relapsed and refractory extranodal NK/T cell lymphoma achieved a 67.9% efficacy rate and a 2-year overall survival rate of 78.6%. Compared with historical data, it significantly improved the prognosis of relapsed and refractory extranodal NK/T cell lymphoma. However, the complete remission rate of sintilimab monotherapy is very low, less than 15%. For highly aggressive malignant lymphomas, complete remission is a prerequisite for long-term survival, so a combination drug strategy is needed.

Whether immunotherapy targeting PD-1 can achieve lasting deep remission depends on the activity of tumor-infiltrating T cells, and most T cells are in an exhausted state due to the special tumor microenvironment. Basic research has shown that epigenetic regulatory drugs (such as deacetylase inhibitors and demethylating drugs) can enhance the effect of immunotherapy by reversing the exhausted state of T cells and upregulating the expression of PD-L1 on the surface of tumor cells.

The results of a prospective clinical trial (SCENT) were announced at the 2020 American Society of Hematology Annual Meeting: Sintilimab combined with chidamide (a deacetylase inhibitor) in the treatment of relapsed and refractory extranodal NK/T-cell lymphoma can achieve a complete remission rate of 44.4%, and the duration of efficacy is significantly longer than that of a single drug. Therefore, the combination of epigenetic regulation and immunotherapy will become the cornerstone of relapsed and refractory extranodal NK/T-cell lymphoma.

The success of immunotherapy in relapsed and refractory extranodal NK/T-cell lymphoma will inevitably promote its research in newly diagnosed extranodal NK/T-cell lymphoma, especially in newly diagnosed advanced patients, but the key is how to organically combine PD-1 monoclonal antibody with traditional chemotherapy.

Recently, prospective studies have shown that the traditional P-GEMOX regimen combined with PD-1 monoclonal antibody is highly effective in the treatment of advanced extranodal NK/T-cell lymphoma without significant increase in toxicity [2]. Therefore, it has pioneered the combination of immunotherapy and chemotherapy for the treatment of extranodal NK/T-cell lymphoma. However, this is only the beginning. More regimens are worth further exploration, especially the combination strategy based on pegaspargase (a key chemotherapy drug for the treatment of extranodal NK/T-cell lymphoma) and PD-1 monoclonal antibody. Although early extranodal NK/T-cell lymphoma can achieve an 80% cure rate, according to the latest NRI prognostic scoring model, the 5-year overall survival rate of early high-risk patients is only about 50%, which still has a lot of room for improvement. Therefore, whether combined immunotherapy on the basis of radiotherapy can further improve the prognosis of patients with early high-risk extranodal NK/T-cell lymphoma has become another hot topic of current research.

Basic research shows that radiotherapy can physically damage tumor tissue, causing it to release more tumor-associated antigens for T cell recognition and killing. Therefore, in theory, it can have a good synergistic effect with PD-1 monoclonal antibody. Recently, there have been prospective studies at home and abroad that use pegaspargase combined with PD-1 monoclonal antibody for induction therapy, sequential synchronous chemoradiotherapy with PD-1 monoclonal antibody, and maintenance therapy with PD-1 monoclonal antibody for patients with suspected micro-residual lesions after radiotherapy (such as plasma EB virus-DNA positive). The successful implementation of this study will create a new model for the treatment of early high-risk extranodal NK/T cell lymphoma.

In short, immunotherapy is rapidly penetrating into all stages of cancer treatment, and even has unexpected effects in chronic viral infection groups. Combination therapy strategies based on immunotherapy will be a research hotspot for extranodal NK/T cell lymphoma in the next few years, but the special toxicity of immunotherapy cannot be ignored. Patients must be managed throughout the process to make patients like Aunt Zhang the biggest beneficiaries of immunotherapy.

[References] [1] Bi XW, Wang H, Zhang WW, Wang JH, Liu WJ, Xia ZJ, Huang HQ, Jiang WQ, Zhang YJ, Wang L: PD-L1 is upregulated by EBV-driven LMP1 through NF-kappaB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma. J Hematol Oncol 2016, 9(1):109.
[2] Cai, J., Liu, P., Huang, H. et al. Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma. Sig Transduct Target Ther. 5, 289 (2020). https://doi.org/10.1038/s41392-020-00331-3 About the author:

Wang Liang

Chief physician and academic leader (in charge of department work) of the Department of Hematology, Beijing Tongren Hospital, Capital Medical University. Graduated from Peking Union Medical College, Doctor of Medicine, selected for the 2020 "Beijing Municipal Health Bureau Young Talent Program"; selected for the 2020 "Tongren Hospital Young Outstanding Talent" program; won the "Respect Life 2017 Honor Doctor-Youth Innovation Award"; member of the 11th Youth Committee of the Hematology Branch of the Chinese Medical Association; Standing Committee Member of the Myeloma Professional Committee of the Chinese Medical Education Association; good at the diagnosis and treatment of lymphoma and other blood system malignancies; presided over a number of projects such as the National Natural Science Foundation, published more than 40 SCI papers, with a cumulative impact factor of >200 points.