ESMO interviews Professor Cen Hong: PD-1 gene knockdown targeted CD19 CAR-T cell therapy relapsed refractory B cell lymphoma prospect may be expected

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The 2022 European Society for Internal Oncology (ESMO) Annual Meeting was held
in Paris from September 9 to 13 local time.
On September 10, several findings were published
at the Proffered Paper session.
Professor Cen Hong of the Affiliated Cancer Hospital of Guangxi Medical University reported the preliminary results of a Phase I study on the treatment of relapsed/refractory B-cell lymphoma using PD-1 gene knockdown, and Professor Cen Hong was invited by Yimai Tong to be interviewed to talk about the main results and significance
of the study.

A study conducted by you and your team explored the efficacy of PD-19 CAR-T cells in the treatment of relapsed/refractory B-cell lymphoma with PD-1 gene knockdown and was selected in the Proffered Paper section of this year's ESMO Annual Meeting.

Professor Cen Hong: At present, CAR-T has achieved good efficacy in the treatment of B-cell lymphoma, acute lymphoblastic leukemia (ALL) and multiple myeloma (MM), and several corresponding products have been approved for marketing
.
There are also two models of targeted CD19 CAR-T approved for B-cell lymphoma in China, but the price is very expensive, the accessibility is relatively poor, and some patients still have relapse
.
The main reasons for the efficacy of CAR-T therapy include the expansion of CAR-T cells in vivo and the duration
of CAR-T cells in vivo.

PD-1 is an immunomonitoring point that is expressed on CD4+ and CD8+ T lymphocytes, and PD-L1
is often expressed on tumor cells.
PD-1/PD-L1 binding can inhibit T cell activation, induce apoptosis of T cells, and affect the efficacy of CAR-T cells
.
Multiple studies have demonstrated that blocking the PD-1/PD-L1 axis can effectively enhance the function of
CAR-T cells.
However, this strategy has been mainly studied in vitro, and our previous study found that after complete knockout of PD-1, cells cannot expand or grow, while CAR-T cells that knock down PD-1 can expand well in vitro without affecting the anti-tumor properties of CAR-T cells, but PD-1 knockdown CAR-T cells have not been fully studied
clinically 。 Therefore, we designed CAR-T cells with short hairpin RNA (shRNA)-mediated PD-1 gene knockdown to reduce PD-1 expression levels on CAR-T cells, reduce PD-L1 binding to tumor cells, and reduce T cell depletion, in order to make CAR-T cells survive longer in vivo and achieve better tumor killing
.

Yi Maotong: Can you please interpret the results of this study?

Professor Cen Hong: This study is a single-arm, Phase I study that explores the initial efficacy and safety of PD-1 gene knockdown targeted CD19 CAR-T cells, and enrolled 16 patients, 12 patients with recurrent refractory B-cell lymphoma (8 cases of diffuse large B-cell lymphoma [DLBCL], 2 cases of follicular lymphoma [FL], 1 case of chronic lymphocytic leukemia [CLL], and 1 case of high-grade B-cell lymphoma [HGBL]).
Four patients were patients with
recurrent refractory ALL.
The overall response rate (ORR) was 62.
5% in all patients, 6 patients (37.
5%) achieved a complete response (CR) (of which 3 were ALL, 2 were DLBCL, and 1 was FL), and 4 (25%) achieved partial remission (PR).

The duration of CR was 36 months, 34 months, and 29 months, respectively, but 3 patients with ALL relapse quickly (2-5 months after CAR-T treatment).

Overall, the efficacy is similar to other CAR-T therapies that have been reported, with some patients with B-cell lymphoma achieving long-term survival, but patients with ALL relapse and subsequent bridging therapies may be required, such as transplantation
.
In terms of safety, 11/16 patients developed cytokine release syndrome (CRS), most (7 cases) were grade 1, 4 cases were grade 2, no grade 3/4 CRS occurred, no treatment-related encephalopathy occurred, no treatment-related death occurred, and overall safety was better
.

The preliminary results of this study show that the efficacy of PD-1 gene knockdown targeted CD19 CAR-T cells in leukemia is not very ideal, please combine the clinical application status of CAR-T, and talk about your opinion?

Professor Cen Hong: For the efficacy of CAR-T cells, the first target selection is very important
.
At present, the most explored target in B-cell lymphoma and leukemia is CD19, targeting CD19 CAR-T cells can enable some B-cell lymphoma patients to obtain long-term survival, and even radical cure
.
However, in acute leukemia, there is rarely a radical effect, and most patients will relapse
after remission.
Why is there such a difference? I think the key is whether CD19 is expressed
on tumor stem cells.
CD19 is widely expressed on mature B-cell tumor stem cells, but may not necessarily be expressed on ALL tumor stem cells, and may only be expressed
on tumor cells with a higher degree of differentiation.
Therefore, the use of CD19 CAR-T cells to treat ALL patients may not be able to destroy tumor stem cells, so there will be recurrence
.

The second is whether CAR-T cells can contact tumor cells in vivo to play a killing role
.
Why are CAR-T cells less effective at treating solid tumors? I think the key to this, in addition to not having a good target, is that CAR-T cells can't fully contact the tumor to attack it
.
Because in the solid tumor microenvironment, CAR-T cells are difficult to contact with tumor cells, in addition, even if contact, the killing ability in the solid tumor microenvironment may be very weak, so the efficacy is poor
.
Of course, the relevant research is still continuing, so there is still a long way to go, and I look forward to more relevant research progress
.

Professor Cen Hong

Doctor of Medicine, Chief Physician, Master Supervisor

Director of the Department of Oncology, Director of the Department of Oncology, Director of the Department of Oncology, Director of the Department of Lymphatic Blood and Pediatric Oncology, Affiliated Cancer Hospital of Guangxi Medical University

Chairman of the Lymphoma Professional Committee of Guangxi Anti-Cancer Association

Member of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association

Member of the CSCO Lymphoma Consortium Expert Committee

Vice Chairman of the Chemotherapy Professional Committee of Guangxi Anti-Cancer Association

Member of the Standing Committee of the Hematology Physician Branch of Guangxi Medical Doctor Association

Member of the Standing Committee of the Hematology Branch of Guangxi Medical Association

He is good at the diagnosis and treatment of lymphohematological tumors, and has rich experience in hematopoietic stem cell transplantation in the treatment of lymphoma, leukemia and multiple myeloma

He has published more than 50 SCI papers, Chinese series journal papers and core journal papers, and presided over and participated in a number of key projects of the National Natural Science Foundation of China, Guangxi Natural Science Foundation, Health Department and Department of Education