Seeing the Risk of Cell Therapy from the Technical Guiding Principles of CAR-T Clinical Risk Management

On January 26, the Center for Drug Evaluation of the State Food and Drug Administration issued the "Technical Guidelines for the Clinical Risk Management Plan for the Application of Chimeric Antigen Receptor T Cell (CAR-T) Therapy Products" (hereinafter referred to as the "Guiding Principles"), the "Guiding Principles".
》describes CAR-T therapeutic products in detail from the aspects of overview, safety, pharmacovigilance, and risk minimization measures of CAR-T therapeutic products
.
Regarding the possible safety risks of CAR-T cell therapy products, the "Guiding Principles" lists in detail the possible safety risks of CAR-T cell therapy products according to the chronological sequence of CAR-T products from production, transportation, processing, administration, follow-up and other processes.
security risks exist
.
This article will elaborate on the risks that may be faced in the application of CAR-T products by sorting out the safety risks of CAR-T therapy listed in the "Guiding Principles"
.
CAR-T therapy has six major risks, including the risk to the patient related to the quality characteristics of the product, storage and distribution, the risk related to the effect of the product, the risk related to the patient's underlying disease or the interaction with the concomitant use of other drugs.
, risks to patients associated with the procedure and mode of administration, risks associated with the management of adverse patient events, and other risks that have not been excluded
.
Among them, the top three risks are the main risks of CAR-T therapy
.
(1) Risks to patients associated with the quality characteristics, storage, and distribution of the product
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Such risks include the risk of disease transmission, the risk of tumorigenicity, and the risks associated with the preparation, storage, transportation and distribution of the product
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For example, the source of T cells, that is, the risk of disease transmission caused by autologous or allogeneic; or the use of gene editing technology to generate non-purpose targeting of the genome, thereby increasing the risk of tumors in patients; in addition, the preservation, freezing and thawing process of CAR-T products Risks related to product stability in CAR-T cells may also affect the biological activity of CAR-T cells
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(2) Risks related to the action of the product
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Such risks include CRS, ICANS, and other neurotoxicity caused by T cell activation.
CAR-T cells attack normal tissue cells expressing target antigens, thereby causing normal tissue damage or immune deficiency; long-term safety risks, such as persistent low Risk of infection, malignancy, and autoimmune diseases caused by globulinemia or agammaglobulinemia
.
(3) Risks related to the patient's underlying disease or interaction with other drugs: such risks include risks related to the patient's own conditions such as tumor burden, combined graft-versus-host disease, etc.
; risks related to pretreatment, Such as the use of chemotherapeutic drugs for lymphocytosis or the use of immunosuppressive agents when dealing with complications; risks associated with expected and unexpected genetic modification of patient or donor cells, such as apoptosis, functional changes, and malignant tumors
.
2021 can be described as the first year of CAR-T cell therapy in China.
Two CAR-T cell therapies have been approved for the market one after another, namely Fosun Kite's Akilence Injection and WuXi Junuo's Ruiki Auremx Injection.

.
From the perspective of targets, both products target CD19, providing a new treatment method for patients with advanced B-cell lymphoma; from the perspective of efficacy, both products have achieved an objective response rate of over 70% in the treatment of DLBCL, and the curative effect Excellent; from a safety point of view, both products are autologous CAR-T cell therapy, free of graft-versus-host disease (GvHD), but both have high levels of cytokine release syndrome (CRS) and neurotoxicity (ICANS)
.
(1) Achilles injection is a targeted human CD19 that Fosun Kite introduced from Kite (a Gilead company) in the United States for technology transfer in China in early 2017, and was authorized to produce locally in China.
Autologous CAR-T cell therapy products
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Approved for marketing in China in June 2021, it is used for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after receiving second-line or above systemic therapy.
It is the first cell therapy product approved for marketing in China
.
The price of Akilunsai injection is as high as 1.
2 million yuan, and it has not yet been included in the national medical insurance catalogue
.
The approval of the DLBCL indication of akirenza injection is based on the positive data of the pivotal clinical study ZUMA-1.
The one-year follow-up results showed that the best overall response rate (ORR) was 82%, and the complete response rate (CR) reached 82%.
54%; median follow-up of 27.
1 months, objective response rate, complete response rate, and sustained response rate were 83%, 58%, and 39%, respectively; follow-up ≥4 years (median, 51.
1 months), median overall survival The period was 25.
8 months, and the 4-year overall survival rate was 44%
.
In terms of safety, 13% of patients in the study experienced cytokine release syndrome (CRS) of grade 3 or higher, and 31% experienced neurological toxicity
.
Common (≥10%) grade 3 or higher reactions include: febrile neutropenia, fever, CRS, encephalopathy, unidentified infection, hypotension, hypoxemia, pulmonary infection
.
Serious adverse reactions occurred in 52% of patients and included: CRS, neurotoxicity, prolonged cytopenias (including neutropenia, cytopenia, anemia) and serious infections
.
Fatal cases of CRS and neurotoxicity occurred in this study
.
(2) Ruiki Orenza Injection is a CD19-targeting CAR-T cell therapy independently developed by WuXi Juno on the basis of JCAR017 from Juno in the United States
.
In September 2021, the NMPA approved Requiorenza injection for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after second-line or more systemic therapy
.
The current price of Ruiki Orensai injection is 1.
29 million yuan, and it has not been included in the national medical insurance list
.
The approval of the DLBCL indication of Ruiqiorenza injection was based on the data of the pivotal clinical study RELIANCE.
The test results showed that among 58 patients with evaluable efficacy, the best objective response rate was 75.
9%, and the best complete response rate was 75.
9%.
was 51.
7%
.
The median follow-up time was 8.
9 months, the median OS was not reached, and the 6-month DOR, PFS and OS rates were 60.
0%, 54.
2% and 90.
8%, respectively
.
In terms of safety, 28 patients (47.
5%) developed cytokine release syndrome (CRS) of different grades
.
Grade 3 and 4 CRS occurred in 2 patients (3.
4%) and 1 patient (1.
7%), respectively, and neurotoxicity occurred in 12 patients, of which only 3 patients (5.
1%) experienced severe (both 3 patients).
level)
.
Although CAR-T cell therapy has achieved an excellent objective response rate for advanced hematological tumors, the safety risk is always like a sword of Damocles hanging over the head.
The frequent occurrence of CRS and ICANS above grade 3 makes the Doctors are walking on thin ice when using CAR-T therapy
.
Legend Bio once explored the convenience of outpatient dosing, hoping to reduce the overall high cost of CAR-T cell therapy, but the risk of outpatient dosing was very worrying for companies, so outpatient dosing was only included in clinical trials.
patients
.
For mild CRS, supportive care, antipyretic therapy, and antibiotic therapy are often used to avoid infection
.
Severe CRS can be treated with corticosteroids, tocilizumab (IL-6), and anti-IL1
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Neurotoxicity (ICANS) can be managed with antiepileptic drugs and routine antimicrobial therapy for infectious complications to prevent neutropenia
.
For the idea of ​​reducing risks including CRS from the source, CAR-NK may be the next city for CAR-T cell therapy
.
CAR-NK does not secrete IL-6, but only a small amount of cytokines such as IFN-γ and GM-CSF, so it is not easy to induce severe cytokine storm
.
According to some currently disclosed clinical data, such as Fate Therapeutics' CAR-NK candidate FT500 targeting PD-1, no CRS, ICANS or GvHD occurred, and the safety is very good
.
The company's other CD19-targeting CAR-NK product, FT596, did not have any level of CRS, ICANS or GvHD, according to the company's data disclosed at ASH in 2020
.
Of course, the current data of CAR-NK is still very limited, and more clinical data disclosure is still needed in the future for further observation
.