2021 ASH big coffee talks about Professor Zhang Mingzhi: PD-1 inhibitors and other research progress in the treatment of NKTCL patients

Background NK/T-cell lymphoma (NKTCL) is a highly aggressive malignant tumor.
Professor Zhang Mingzhi and his team from the Lymphoma Center of the First Affiliated Hospital of Zhengzhou University have selected three NKTCL-related studies in the 63rd American Society of Hematology this year.
(ASH) Poster presentation of the annual meeting
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Yimaitong sincerely invites Professor Zhang Mingzhi to accept an interview to discuss the latest developments in NKTCL treatment based on research results and clinical experience
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Yimaitong: Patients with refractory/relapsed extranodal NKTCL have a poor prognosis and lack effective treatment
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You and your team carried out a phase II clinical trial of tislelizumab (PD-1) combined with chidamide, lenalidomide and etoposide in the treatment of refractory/relapsed extranodal NKTCL, and were shortlisted for this year's ASH conference Can you tell me the circumstances under which you decided to carry out this research? Professor Zhang Mingzhi NKTCL is a type of tumor closely related to Epstein-Barr virus infection
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Epstein-Barr virus infection leads to increased expression of PD-L1, which is the basis of the effect of PD-1 inhibitors
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A Hong Kong study of 7 PD-1 inhibitors for the treatment of NKTCL has an effective rate of 100%, while the 7 cases of NKTCL we reported using PD-1 inhibitors have an effective rate of only 50%
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Seven follow-up studies of PD-1 inhibitors in the treatment of NKTCL proved that the average effective rate of PD-1 inhibitors in the treatment of NKTCL is about 50%, and the complete remission (CR) rate is 20%-30%
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This shows that the PD-1 inhibitor alone is effective in treating NKTCL, but the effective rate is not high
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Some authors have discussed this, saying that although PD-L1 is expressed, it is affected by many factors, such as tumor mutational burden (TMB), microsatellite instability distribution (MSI), tumor microenvironment, and immune status in the body
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Therefore, based on the expression of PD-L1 alone may not obtain better curative effect
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When PD-1 inhibitors were first launched on the market, we had a patient treated with PD-1 inhibitors, and the results were encouraging
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After the failure of the first, second, and third-line treatments, a large number of nodules appeared on the skin of the patient.
After chemotherapy, the nodules were necrotic, and some drug-resistant tumor cells appeared underneath the necrosis and scab, which could not be shed by chemotherapy alone
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After using PD-1 inhibitor, the necrosis and scab fell off completely
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The current patient's condition is very good, but as just said, the effective rate of PD-1 inhibitors to treat NKTCL is about 50%, and the CR rate is 20%-30%, which is still not satisfactory
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In addition to the mechanism of action, there is currently an exploration of using PD-1 inhibitors for combination therapy
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For example, Professor Huang Huiqiang used PD-1 inhibitors in combination with epigenetics drug Chidamide and found that PD-1 inhibitors synergistically increased Chidamide
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At present, patients with relapsed and refractory NKTCL (R/R NKTCL) who are treated with PD-1 inhibitor + Chidamide combined therapy show synergistic effect
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However, PD-1 inhibitors and chidamide have slow onset of action.
As a highly aggressive tumor, R/R NKTCL sometimes develops very fast.
It may be that the patient's condition has developed rapidly or died before the drug is effective.

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Therefore, we consider applying some fast-acting drugs on the basis of these two drugs, such as etoposide (VP-16) and lenalidomide
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VP-16 also acts on macrophages, which can treat and prevent hemophagocytic syndrome
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Lenalidomide can regulate immunity, adjust tumor microcirculation, and promote tumor cell apoptosis
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These four drugs complement each other and act as a synergistic anti-R/R NKTCL
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Therefore, we launched a prospective multi-center Phase II trial nationwide last year [1], which proved that the PD-1 inhibitor combined with Chidamide, lenalidomide, and VP-16 was the first in R/R NKTCL.
There is a very high response rate during treatment, and adverse reactions are safe and controllable
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This research was also presented in a poster at this year's ASH conference
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Yimaitong: This research has achieved very good preliminary results.
Could you please introduce the latest research results and share your interpretation of the research results? Professor Zhang Mingzhi From July 2020 to July 2021, we enrolled 10 patients.
Among the 8 patients with evaluable R/R NKTCL, 7 patients (87.
5%) achieved remission, of which 5 patients (62.
5%) To reach CR, the median time to initial remission is 6 weeks (6-12 weeks)
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Ten patients reported treatment-related adverse reactions (TRAE)
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The most common TRAEs were neutropenia (10 cases), thrombocytopenia (4 cases), elevated transaminases (3 cases), and nausea (4 cases)
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Two patients had immune-related adverse events of hypothyroidism
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These adverse events are mostly grade I-II
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No deaths were found in this study
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So far, 20 patients have been enrolled in clinical observation, and the curative effect has basically maintained the above-mentioned level
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I think it is better to be able to obtain such research results
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There is currently a teenage boy who has been using PD-1 inhibitors for more than a year and has regular follow-up visits.
He is in good condition
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On the basis that PD-1 inhibitors have shown such a good effect, we are considering the next step and start to promote them nationwide
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Yimaitong: We are concerned that in addition to this clinical study, you and your team have two preclinical studies on NKTCL treatment.
What drugs did these two studies explore? What new research directions can be provided for NKTCL treatment? Professor Zhang Mingzhi is a study on the combination of VP-16 and Chidamide [2]
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Chidamide is an epigenetic drug that has an effect on T cells and NK cells
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VP-16 can prevent and treat NKTCL-related hemophagocytic syndrome
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We first did clinical research and then conducted basic experiments.
The results of the study proved that Chidamide and VP-16 both have a dose- and time-dependent inhibitory effect on NKTCL cells, and the combination of the two has a synergistic effect
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The combination of Chidamide and VP-16 can cause DNA damage, cell cycle G2/M phase block, decrease of mitochondrial membrane potential, restoration of epigenetic modification, promote apoptotic cell death, and inhibit the growth of NKTCL in vivo
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The results of this research were presented at this year's ASH conference
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The other is a study on bendamustine [3]
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Bendamustine, as a bifunctional alkyl chemotherapeutic drug, has achieved very good curative effects in the treatment of B-cell lymphoma in recent years, but it has been used less on NKTCL and reported less
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We use bendamustine to treat NKTCL patients, and study the efficacy of bendamustine based on the results of cell apoptosis and cell growth.

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Studies have found that bendamustine can significantly inhibit NKTCL both in vitro and in vivo.
It is likely that NKTCL cell apoptosis and cell cycle arrest can be caused by activating DDR and inhibiting STAT3
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This is only the basic research in the current laboratory.
In the future, opening up new therapeutic approaches for PD-1 inhibitors and new drug combination therapy is our new research direction
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Professor Zhang Mingzhi, PhD supervisor, Director of Cancer Center, The First Affiliated Hospital of Zhengzhou University, Member of the Standing Committee of the Chinese Medical Association Oncology Branch, Member of the Standing Committee of the Chinese Medical Association Oncology Branch, Standing Committee Member of the Chinese Medical Association Oncology Branch, Translational Medicine Group Leader, Chinese Society of Clinical Oncology (CSCO) China Vice Chairman of the Expert Committee of the Anti-Lymphoma Alliance Deputy Director of the Lymphoma Subcommittee of the Hematological Oncology Committee of the Chinese Society of Geriatrics Deputy Director of the Lymphoma Subcommittee of the China Precision Medicine and Hematology Professional Committee Vice Chairman of the Oncology Branch of the Henan Medical Association Deputy Director of the Oncology Branch of the Henan Medical Association Henan Province Director of the Lymphoma Professional Committee of the Anti-Cancer Association Henan Provincial Department of Science and Technology Outstanding Talents Undertake 4 National Natural Science Foundation, 19 provincial and departmental scientific research projects, published 315 academic papers (159 SCI articles), and won 6 provincial science and technology awards References: [1]ASH 2021,abstract#1368.
[2]ASH 2021,abstract#3987.
[3]ASH 2021,abstract#2945.
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