i Hope time Professor Wang Yusheng's team: CAR-T therapy for the treatment of digestive tract tumors in China, the future can be expected!

Not long ago, the results of a CAR-T therapy for Claudin18.
2-positive gastrointestinal tumors led by Professor Shen Lin of Peking University Cancer Hospital were published
in the journal NATURE MEDICINE.
This study is not only the largest clinical study of solid tumor CAR-T to date, but also the best reported
efficacy of CAR-T in the treatment of solid tumors.
In this regard, Shanxi i Hope College invited the team of Professor Wang Yusheng of Shanxi Provincial Cancer Hospital of Shanxi Hospital of Chinese Academy of Medical Sciences to interpret the study
.
Details are as follows:

Study details

background

The treatment of advanced gastrointestinal tumors is mainly based on chemotherapy, molecular targeted therapy and other drug therapy, but it faces the problems of limited efficacy of chemotherapy, a small number of
molecularly targeted drugs, and the overall treatment effect has reached a bottleneck.
In recent years, immune checkpoint inhibitors represented by anti-PD-1/PD-L1 antibodies have achieved great success in the treatment of esophageal cancer and gastric cancer, which has improved the prognosis
of advanced gastrointestinal tumors.
At the same time, CAR-T (Chimeric antigen receptor T cell) therapy has also achieved remarkable success in the treatment of hematologic malignancies, and its application in solid tumors has also attracted much attention
。 On May 9, 2022, the team of Professor Shen Lin of Peking University Oncology Hospital published an article entitled "Claudin18.
2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results" online, targeting CLDN18.
2 CAR-T Results of an interim analysis of cells (CT041) in an ongoing, nonblind, single-armed, phase I clinical trial (NCT03874897) in patients with CLDN18.
2-positive digestive tumors, including safety after CT041 infusion, efficacy of CT041, pharmacokinetics, and immunogenicity
.

method

The study was conducted from March 26, 2019 to April 8, 2021, enrolled participants aged 25 to 74 years (median 53 years), immunohistochemically confirmed tumor tissue expression CLDN18.
2 positive (expression intensity ≥2+, positive tumor cell rate ≥40%), ECOG score 0 or 1 and adults with
advanced digestive cancer who have received at least one standard of treatment.
A total of 37 patients were included in the interim analysis, of which 28 patients were gastric or gastroesophageal junction tumors, 5 patients with pancreatic cancer, and 4 patients were other types of digestive tumors
.
These patients received a CT041 infusion and completed a safety, efficacy, and pharmacokinetic assessment
for at least 12 weeks after the first infusion.


Studies include dose-increasing/decreasing phases and dose-extension phases
.
During the dose increment/decrement phase, patients received CT041 cell infusions at doses of 2.
5×108 (28 cases), 3.
75×108 (6 cases), or 5.
0×¹⁰⁸ (3 cases),
respectively.
A 2.
5×¹⁰⁸ CT041 cell dose is ultimately recommended for the dose expansion phase
.

The primary endpoints of the study were safety and tolerability of CT041, and the secondary endpoints were efficacy and pharmacokinetics
.
Figure 1 Research flowchart

outcome

In terms of safety, the safety and tolerability
of this treatment are assessed 28 days after the first infusion of CT041.
Within 28 days after the first infusion, no predefined dose-limiting toxicity (DLT)
was observed.
However, in 1 patient (Pt02) at the dose level of 5.
0×¹⁰⁸, the tumor resolves rapidly after the second infusion, and grade 4 gastrointestinal bleeding
occurs.
The most common AEs of grade 3 and above are hematological toxicity, with the incidence of leukopenia being 83.
8% (31/37), neutropenia 67.
6% (25/37), anemia 40.
5% (15/37), and thrombocytopenia 16.
2% (6/37).

Hematological toxicity occurs within 28 days of the first infusion, with a median recovery time of 4 to 9 days
.
In terms of digestive response, 4 patients (10.
8%) reported reversible grade 3/4 gastrointestinal toxicity, including grade 4 gastrointestinal bleeding and 3 cases of abdominal pain, obstructive pancreatitis and gastric mucosal injury, all of which improved
after symptomatic treatment.
A patient with anaphylactic shock at the second infusion recovered within 30 minutes after adrenal hormone and glucocorticoid therapy, and it should be noted that the patient had a history of
allergies to anti-PD-1 antibodies, platinum and other drugs.


Grade 1 or 2 cytokine release syndrome (CRS) occurred in 35 of the 37 patients (94.
6%)
.
In the first cycle of treatment, the median onset of CRS is 2 days after infusion, and the median duration is generally 6 days
.
There is no clear dose-response relationship between the incidence and severity of CRS, and there is no significant relationship between cancer type and CRS incidence and severity
.
In the study, it was found that the median ferritin peak in patients with grade 2 CRS was higher than that in patients with grade 1 CRS (P = 0.
0269), suggesting that ferritin peak can be used as a clinical indicator
of CRS grading.
For CRS treatment, 27 patients received tocilizumab and 4 patients were alleviated by glucocorticoid therapy, and no immune effector cell-associated neurotoxicity syndrome (ICANS) or treatment-related deaths
were observed.

In terms of efficacy, 36 of the 37 patients had measurable target lesions, of which 30 (83.
3%) had tumor regression, with overall response rate (ORR) and disease control rate (DCR) reaching 48.
6% (95% CI, 31.
9, 65.
6) and 73.
0% (95% CI, 55.
9, 86.
2), respectively, and a median progression-free survival (mPFS) of 3.
7 months (95% CI, 2.
6, 5.
4), respectively.
The overall lifetime (OS) rate at 6 months was 80.
1% (95% CI, 62.
5, 90.
0
).
Among them, the ORR and DCR of gastric cancer patients reached 57.
1% (95% CI, 37.
2, 75.
5) and 75.
0% (95% CI, 55.
1, 89.
3), mPFS was 4.
2 months (95% CI, 3.
7, 9.
2), and the overall survival rate of 6 months was 81.
2% (95% CI, 60.
3, 91.
8),
respectively 。 Of the 16 patients with gastric cancer who responded to CT041, 14 patients received PR at week 4 after the first injection of CT041, 1 patient responded in week 8, and 1 patient responded
after the second infusion.
In subgroup analyses, ORR was as high as 70% in patients with Lauren enteric type, and 63%
in patients with high expression of CLDN 18.
2 (immunohistochemistry 2+ or 3+).

Correlation between different T cell subsets and clinical efficacy was an exploratory endpoint
for this study.
After evaluating the efficacy of CT041 infusion in 28 patients with gastric cancer, the study found that patients with a lower proportion of CD45RA/CCR7+ cells were more likely to obtain longer PFS (P=0.
0058), but there was no statistically significant correlation
between any one T cell subpopulation and OS.
Figure 2 Efficacy results

conclusion

This study preliminarily shows that CT041 has good safety and efficacy
in cldn18.
2-positive digestive system tumors, especially in patients with gastric cancer.

i Hope time

i Founder of Hope Medicine

Professor Qin Haifeng

Review the expert team

Professor Wang Yusheng

• Shanxi Hospital of Chinese Academy of Medical SciencesShanxi HospitalShanxi Provincial Cancer Hospital

• Chief of the Department of Gastroenterology I Chief Physician

• Ph.
  D.
  in Oncology Master Supervisor

• Vice Chairman of the Ethics Committee of Shanxi Provincial Cancer Hospital

• Deputy Director of Shanxi Provincial Gastric Cancer Diagnosis and Treatment Center

• Member of the Gastric Cancer Quality Control Expert Committee of the National Cancer Quality Control Center

• Member of the Special Committee for Multidisciplinary Diagnosis and Treatment of Oncology of the Chinese Anti-Cancer Association

• Member of the Special Committee on Tumor Hepatology of the Chinese Anti-Cancer Association

• Member of the CSCO Pancreatic Cancer Committee

• Member of the CSCO Gastrointestinal Stromal Tumor Committee

• Member of the Standing Committee of the Esophageal Cancer Committee of the Beijing Society for Cancer Prevention and Control

• Member of the Standing Committee of the Oncology Committee of the Chinese Association of Research Hospitals

• Chairman of the Youth Committee of the Tumor Chemotherapy Professional Committee of Shanxi Anti-Cancer Association

• Leader of the liver cancer group of the Hepatologist Branch of Shanxi Medical Doctor Association

• Vice Chairman of the Youth Committee of Hepatology Branch of Shanxi Medical Doctor Association

• Vice Chairman of the Youth Committee of the Liver Cancer Committee of Shanxi Anti-Cancer Association

• Vice Chairman of the Youth Committee of the Colorectal Cancer Professional Committee of Shanxi Anti-Cancer Association

• Member of the Standing Committee and Secretary General of the Oncology Professional Committee of Shanxi Medical Association

Professor Zhang Ninggang

• Deputy Chief Physician, Department of Gastroenterology, Shanxi Provincial Cancer Hospital, Doctor of Medicine

• He is a member of the Youth Committee of the Oncology Branch of the Chinese Medical Association

• Standing Committee Member of the Youth Committee of the Esophageal Cancer Professional Committee of the Beijing Society for Cancer Prevention and Treatment

• Vice Chairman of the MDT Committee of Shanxi Gastrointestinal Surgeon Branch

• Member of the Youth Committee of the Chemotherapy Professional Committee of Shanxi Anti-Cancer Association

• Member of the Shanxi Anti-Cancer Association Geriatric Oncology Professional Youth Committee

• He is a member of the 4th Committee of the Hepatology Physicians Branch of Shanxi Medical Doctor Association

• Member of the Colorectal Cancer Professional Committee of Shanxi Anti-Cancer Association

• Member of the Youth Committee of the 6th Digestive Disease Committee of Shanxi Medical Association, Shanxi Provincial Gastrointestinal and Pancreatic Nerve Endocrine Oncology Professional Committee

Professor Wang Yusheng: China is a big country with gastric cancer, and the proportion of advanced gastric cancer is high, and the prognosis is poor
.
The efficacy of previous chemotherapy drugs has reached a bottleneck, the target drugs such as trastuzumab are limited to the number of people, and advanced gastric cancer urgently needs new treatment drugs and methods
.
CHECKMATE-649, ORIENT-16 and other domestic and foreign clinical studies have confirmed the effectiveness of anti-PD-1 antibodies in the treatment of advanced gastric cancer, turning a new chapter
in the treatment of gastric cancer with immune-related drugs.
In addition, CAR-T therapy as the representative of cellular immunotherapy in the treatment of hematological tumors to achieve very good efficacy, compared with general chemotherapy and monoclonal antibody targeted drugs, CAR-T therapy can be applied alone, and the efficacy is long-lasting, a single infusion can play a long-term role
in the body to kill tumors.
However, due to the difficulty of CAR-T infiltration in solid tumors and the immunosuppressive microenvironment, the research progress of CAR-T in solid tumors is slow
.

CLDN18.
2 is a member of the Claudin protein family, located on the surface of the cell membrane, under normal circumstances, only low levels of expression in gastric mucosal differentiated epithelial cells, but in the pathological state, Claudin 18.
2 expression in a variety of tumors significantly upregulated, a number of studies have shown that CLDN18.
2 can be ectopic activation in gastric cancer, pancreatic cancer, ovarian cancer, lung cancer, bile duct cancer and other tumors, CLDN18.
2 expression of the population accounted for a higher proportion of gastric cancer (42%-86%)
。 As one of the few ideal targets for solid tumors, CAR-CLDN18.
2 CAR-T treatment has attracted much attention
.
The CAR-CLDN18.
2CAR-T (CT041) therapy carried out by Professor Shen Lin's team of Peking University Cancer Hospital has shown good efficacy and excellent tolerance in advanced gastrointestinal tumors, especially gastric cancer, which is also China's independent research and development, the world's first clinical trial license for CLDN18.
2-targeted CAR-T cell therapy, so that the application of CAR-T therapy in solid tumors has ushered in the dawn!

This phase I study explored the safety and tolerability of CT041, and the results showed that CT041 was well tolerated in patients with digestive CLDN18.
2 positive, with no reported dose-limiting toxicity (within 28 days of the first infusion), treatment-related death, or AEs
leading to study withdrawal.
All patients developed the expected transient hematologic toxicity
.
CLDN 18.
2 is expressed in the epithelial epithelium of the gastric mucosa, but irreversible gastrointestinal damage has not been observed
.
CAR-T therapy has observed a high-profile severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in hematologic tumors, not in this study, only grade 1/2 cytokine release syndrome (CRS).

It is believed that the good safety of this study can bring great confidence
to researchers to carry out follow-up phase II.
/III studies and the application of CAR-T in solid tumors.

The secondary endpoint CT041 (Claudin18.
2 CAR-T) of this study was also as effective as expected
.
Taking the gastric cancer that accounts for the majority of the group as an example, the ORR of CT041 is close to 60%, the DCR rate is 75%, and the overall survival rate of 6 months is 81.
2%, which is also significantly improved
compared with traditional treatment.
The patients included in this study were all patients with posterior gastric cancer who had failed previous treatment, 25 (89.
3%) had received at least two treatment lines or at least fluoropyrimidine, oxaliplatin and paclitaxel triple, and 12 (42.
9%) had received anti-PD-1/PD-L1 antibody therapy
。 In previous clinical reports, navurizumab (ATTRACTION 2 study), pabolizumab (KEYNOTE-059 study, cohort 1), TAS 102 (TAGS study), and apatinib were used for third-line gastric cancer with ORRs of 11.
2%, 13.
3%, 4%, and 1.
7%, respectively, mPFS between 1.
6-2.
6 months, and OS for no more than 6 months
。 From the characteristics of the enrolled patients, the pathological type of gastric cancer patients in this study was 42.
9% of the patients with imprinted cell carcinoma, 57.
1% of the patients with diffuse/mixed type Lauren, and 67.
9% of the patients were accompanied by peritoneal metastasis, all of which were patients with gastric cancer with
previous refractory and poor prognosis.
In addition, it is worth noting that 50% (6 patients) of the 12 patients included in this study who had previously received anti-PD-1/PD-L1 antibody therapy responded to CT041, while for patients with negative PD-L1 expression, the ORR after CT041 treatment was close to 70%.

It is shown that the efficacy of CT041 is not related to the expression of PD-L1 in tumors, and the efficacy is not affected by the failure of previous anti-PD-1/PD-L1 antibody therapy
.

The study carried out by Professor Shen Lin's team is not only the largest clinical study of solid tumor CAR-T to date, but also the best report on the efficacy of CAR-T in the treatment of solid tumors, showing the good safety and efficacy of
CT041 in Claudin18.
2 positive gastrointestinal tumors.
This study points in a new direction
in the treatment of gastrointestinal tumors.
We also look forward to the results of subsequent Phase II.
/III clinical studies, and we look forward to the brilliance of CAR-T therapy in the treatment of solid tumors, bringing hope
to more patients.

References

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Claudin18.
2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results.
Nat Med.
2022 Jun; 28(6):1189-1198.

2.
Neelapu SS, Locke FL, Go WY.
CAR T-Cell Therapy in Large B-Cell Lymphoma.
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11520.
Epub 2020 Apr 7.
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4.
 NCCN Guidelines for Gastric Cancer.
Version 2.
National Comprehensive Cancer Network.
  (2022).

Reviewer: Xiaoyuan Typesetting: Xiaoyuan Execution: Xiaoyuan