Professor Zhong Diansheng and Professor Meng Fanlu: "Talking" about the immunotherapy of advanced solid tumors, "drawing" a new way for long-term survival

*Only for medical professionals to read for reference.
Domestic PD-L1 Nanobody brings more options and benefits for advanced solid tumor treatment.

In recent years, immune checkpoint inhibitors represented by PD-1/PD-L1 antibodies have become an important means of tumor treatment.

Envolimab, the first subcutaneously injected PD-L1 nanobody independently developed in my country, has multiple specific advantages over traditional PD-1/PD-L1 antibodies and shows good anti-tumor activity.

The "medical community" specially invited Professor Zhong Diansheng and Professor Meng Fanlu from the General Hospital of Tianjin Medical University to share the development of immunotherapy and clinical practice experience in medication.

 MSI-H/dMMR: Open a new way for solid tumor immunotherapy without limitation to cancer types.
Professor Zhong Diansheng pointed out: "Tumor treatment has gone through the stages of chemotherapy, anti-vascular therapy, and targeted therapy.

In recent years, tumor immunotherapy has developed rapidly, since 2011 Since the first CTLA-4 inhibitor was approved for the treatment of advanced melanoma, immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1 have undergone sufficient exploration and clinical verification.
Several tumor types have achieved certain success, which has greatly changed the strategy and pattern of tumor treatment.

Unlike chemotherapy and targeted therapy, immunotherapy is a new type of treatment that activates the human immune system to kill tumors.

Currently on the market in China There are 8 PD-1/PD-L1 antibodies in total, including 6 PD-1 antibodies (2 imported, 4 domestic) and 2 PD-L1 antibodies (all imported), which brings great benefits to clinical treatment Improvement, and with the reduction of drug prices, its clinical applications are becoming more and more extensive.

” Professor Zhong Diansheng also pointed out: “While immunotherapy brings revolutionary progress, it also brings many new problems and challenges.

At present, immunotherapy , Especially immune monotherapy, the effective rate is low, about 15%-20%.

Therefore, it is particularly important to search for immunotherapy biomarkers and screen the population with advantages in immunotherapy.

In the treatment of immune checkpoint inhibitors, PD-L1 expression is commonly used, but it is mainly used in lung cancer; tumor mutation burden (TMB) is limited by algorithms and other reasons, and is not widely used and accepted.

"In 1993, first described in the literature for colorectal cancer (CRC) microsatellite instability phenomenon (MSI) exists, open the MSI exploration precedent.

Since then, researchers in multiple types of cancer also found that the phenomenon.

A Research [1] detected more than 200,000 microsatellite sites in the exons of 5930 tumor samples containing 18 cancer types, and found that microsatellites are highly unstable in different cancer types (MSI-H) There is a big difference in the incidence, among which the highest incidence of endometrial cancer is 30%, and the incidence of gastric cancer and colon cancer is 19%.

Figure 1.
The incidence of MSI-H in 18 cancer types.
Clinical studies have confirmed that MSI-H/ Mismatch repair deficiency (dMMR) can effectively predict whether patients with advanced solid tumors will benefit from immune checkpoint inhibitor therapy, and has nothing to do with specific cancer types [2].

Based on this, the U.
S.
Food and Drug Administration (FDA) approved in 2017 Pembrolizumab is used for the treatment of patients with advanced or metastatic solid tumors of MSI-H/dMMR.
This is the first time in the history of the FDA to approve drug indications regardless of tumor source and tumor histology.

Since then, MSI-H/ dMMR has also officially entered the clinic and has become a more successful pan-tumor marker for predicting the efficacy of PD-1/PD-L1 antibodies.

 Professor Zhong Diansheng pointed out: “Pembrolizumab was the first to be approved for the second-line and above treatment of MSI-H/dMMR entities.
Tumor indications, this indication is not limited to tumor types, only the efficacy marker MSI-H/dMMR needs to be tested.

In view of the low incidence of MSI-H/dMMR in lung cancer, high incidence in gastric cancer and colorectal cancer, for this part of the population, the Department of Oncology, Tianjin Medical University General Hospital of our center has conducted an exploration of envolimab, and the results show Better treatment effect.

"Domestic PD-L1 nanoantibody overtakes corners, bringing more choices for advanced solid tumors.
Envolimab (KN035) is a PD-L1 nanobody independently developed in China, compared to PD-1 that is already on the market and under development.
/PD-L1 antibody has unique advantages.
It
not only has the advantages of high efficacy and low toxicity of PD-L1 antibody drug, but also has the characteristics of small molecular weight, high affinity, high stability, and subcutaneous injection.

 Professor Zhong Diansheng said: "En Wollimumab is a very characteristic drug.
The PD-1/PD-L1 inhibitors currently in use are all Ig-G1 or Ig-G4 antibodies, while Envolimab has a unique camel antibody structure without lightness.
The chain has only heavy chains and has a small molecular weight.
It can be injected subcutaneously and is very convenient to use.

Unlike other approved PD-1 antibody development roads in China, Envolimab did not choose lymphoma and melanoma as the research population, but directly used MSI-H/dMMR as the research population.

Clinical research data showed that the ORR of envolimab as a single agent for MSI-H/dMMR patients above second-line treatment was 42.
7%, the median progression-free survival was 11.
1 months, and the 1-year overall survival rate was 74.
6%.

With good clinical data performance, Envolimab can overtake in corners and is expected to become the first immunotherapeutic drug approved for MSI-H/dMMR treatment in China.

Table 1.
Efficacy of Envolimab in the treatment of Chinese MSI-H/dMMR solid tumors For the clinical application of Envolimab, Professor Meng Fanlu from the Department of Oncology, Tianjin Medical University General Hospital pointed out: "Compared with other immunotherapy drugs, Envolimab does not need to be stored in a refrigerator at low temperature, and storage at room temperature can save medical costs.
In addition, Envolimab does not require intravenous infusion and is very convenient for subcutaneous injection.
It also performs well in terms of safety and has mild adverse reactions.

The Phase I clinical study of Envolimab showed that the ORR of patients treated with Envolimab was 20%; of these, two patients with cholangiocarcinoma achieved PR.
The immunotherapy of patients with cholangiocarcinoma has not yet been approved for indications.
The monoclonal antibody showed good activity.

In our hospital, 20 patients with advanced solid tumors were enrolled in the phase Ib study of envolimab.
Among them, 19 patients received envolimab 2.
5 mg/kg2 treatment and 1 patient received 5 mg/kg2 treatment.

During the treatment period, only 1 patient had severe immunotherapy adverse reactions, and the incidence of other common adverse reactions of immunotherapy such as interstitial pneumonia, hypothyroidism, liver and kidney damage was relatively low.

In the clinic, I encountered a patient with MSI-H ileocecal tumor recurrence after surgery.
The patient had metastasis to the abdominal lymph nodes.
There was a 5-6cm mass surrounding the abdominal aorta next to the abdominal aorta and received envolimab treatment.
Partial remission was obtained afterwards, and there were no adverse reactions related to immunotherapy.
The progression-free survival period has been as long as 32 months.
The maintenance treatment is still ongoing and long-term survival has been achieved.

"Case information patient, male, 61 years old.

In May 2017 due to "diarrhea and abdominal distension with pain in the right lower abdomen", abdominal CT showed: ileocecal space-occupying lesions, mesenteric lymph node enlargement; tumor marker: CEA 7.
29ng/ ml.

On May 21, 2017, “right hemicolectomy + abdominal lymph node dissection + terminal ileum transverse colon anastomosis” was performed.
Postoperative pathology: mucinous adenocarcinoma, some of which were signet ring cell carcinoma, invaded the entire thickness of the intestinal wall, MLH1 , PMS2 is weakly positive, MSH2 and MSH6 are negative, Ki-67 is about 70%, margin (-), intestinal lymph node 5/17.

From June 2017 to December 2017, XELOX chemotherapy was given for 8 cycles (Oxali Platinum 200mg d1 + capecitabine 1.
5g bid d1-14), no obvious adverse events were
observed during the treatment period.
Routine re-examination of abdominal CT after operation in March 2018 showed that the lymph nodes adjacent to the abdominal aorta were enlarged, not except for metastasis.

2018 PET-CT examination on March 28 showed that the metabolism of multiple lymph nodes in the abdominal cavity was increased, and metastasis was considered.

Intensified CT examination of the whole abdomen on June 12, 2018 showed that the para-aortic lymph nodes in the abdominal aorta were significantly larger than before.

 Figure 2.
Imaging examination 2018 The genetic test prompt on August 25, 2015: MSI-H.

 Table 2.
The results of the test items were included in the envolimab study in September 2018.
After 3 months of treatment with envolimab, the lesions shrank, and the efficacy was assessed as partial remission.

 Figure 3.
Imaging examination before and after envolimab treatment Professor Fanlu Meng said: Compared with other tumors such as lung cancer, gastrointestinal tumor immunotherapy is relatively insensitive.

A number of studies have confirmed that MSI-H is an effective biomarker for predicting the efficacy of immunotherapy for patients with colorectal cancer, and has since opened the way for the development of immunotherapy for this type of population.

At present, the MSI-H population has benefited from research related to end-line, second-line, first-line, and even neoadjuvant therapy, and the effective rate is constantly improving.

 The Phase II study of envolimab in the treatment of MSI-H/dMMR solid tumors showed that the ORR of patients with colorectal cancer who had previously been treated with fluorouracil and oxaliplatin or irinotecan was 43.
1% , The median PFS reached 7.
2 months, and the withdrawal rate due to adverse reactions was only 1% [3].

The good anti-tumor activity and safety of Envolimab in MSI-H/dMMR CRC increase confidence in the clinical treatment of MSI-H intestinal tumors.

 This patient was a patient with ileocecal cancer, who relapsed after surgery and XELOX chemotherapy.
Genetic testing indicated MSI-H, so envolimab immunotherapy was given.

After 3 months of treatment with envolimab, the lesions shrank, and the efficacy was evaluated as partial remission.
After continuous treatment for 2 years, the patient maintained partial remission for 32 months, and there were no immunotherapy-related adverse reactions during the treatment period, which confirmed Envole The monoclonal antibody has a good effect in the treatment of recurrent intestinal tumors.

Expert Profile Professor Zhong Diansheng Director, Doctoral Supervisor, Professor, Chief Physician of the Department of Oncology, General Hospital of Tianjin Medical University, Member of the Chinese Medical Association Oncology Branch Member of the Chinese Medical Association Respiratory Branch Lung Cancer Group Member, Chinese Anti-Cancer Association Tianjin Chemotherapy Professional Committee Vice Chairman China Anti-Cancer Leader of the Lung Cancer Group of the Tianjin Targeting Professional Committee of the Association, Vice Chairman of the Tianjin Precision Medicine Specialty Committee of the Chinese Medical Doctor Association, as the editor of "Chinese Journal of Lung Cancer", "Tianjin Medicine", "International Journal of Oncology", "International Respiratory Journal" and other journals Committee, successively published more than 40 papers in English in "Cancer Research" and other magazines, published more than 90 papers in total, presided over four research projects of the National Natural Science Foundation of China and two projects funded by the Tianjin Natural Science Foundation, and participated in major national and Tianjin research projects.
Topic 6 Dr.
Meng Fanlu, Deputy Chief Physician, Department of Oncology, Tianjin Medical University General Hospital, Tianjin Medical University General Hospital "Young Technical Backbone" Member of the Oncology Branch of China Healthcare International Exchange Promotion Association Member of the Beijing Medical Award Foundation Lung Cancer Medicine Youth Expert Committee Tianjin Member of the Respiratory Disease Professional Committee of the Municipal Integrative Chinese and Western Society Member of the Tianjin Anti-Cancer Association Integrative Chinese and Western Medicine Tumor Therapy Professional Committee Member of the Chinese Society of Clinical Oncology Member of the Chinese Society of Cell Biology Published more than 10 papers included in SCI and domestic core journals Hosted or participated in the country and the province Participated in more than 40 international/domestic multi-center clinical research on 5 subjects of level-level subjects: [1] Ronald J Hause, Colin C Pritchard, Jay Shendure, et al.
Classification and characterization of microsatellite instability across18 cancer types[J].
Nat Med , 2016, 22: 1342-1350.
[2] Le, DT, JN Uram (2015).
PD-1 Blockade inTumors with Mismatch-Repair Deficiency.
New England Journal of Medicine372(26): 2509-2520.
[3] Lin Shen et al.
Journal of Clinical Oncology 38,no.
15_suppl (May 20,2020) 3021-3021.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform