ASH's new "shi" Li Song Yuqin and Zhang Huilai: Double-antibody Glofitamab helps T-cell immunotherapy start a new journey, and the unique administration method effectively improves the safety profile

The 63rd annual meeting of the American Society of Hematology (ASH), the largest international event in the field of hematology in the world, was held in Atlanta, USA from December 11 to 14, 2021
.

The publication of a number of major studies and the latest results at the ASH annual meeting has greatly promoted the development of the field of hematology, and provided an opportunity for academic exchanges to promote the diagnosis and treatment of blood system diseases for clinicians
.

Just in time, closely following international hotspots and focusing on the frontiers of diffuse large B-cell lymphoma (DLBCL) and immunotherapy, iMaiTong sincerely invites Professor Song Yuqin from Peking University Cancer Hospital and Professor Zhang Huilai from Tianjin Medical University Cancer Hospital to share T cells The development ideas of therapy, the latest clinical progress and unique safety advantages of the bispecific antibody Glofitamab (Glofit for short) are for readers
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Key content: T cell immunotherapy is an important direction for the development of tumor immunity in the future, and safety management needs to be paid attention to on the premise of ensuring efficacy
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Glofit is pretreated with otuzumab (Gpt), which provides better clinical application characteristics: lower cytokine release levels and effective mitigation of cytokine release syndrome (CRS)-related toxicity
.

ASH has added a number of new certificates, and Glofit monotherapy and combination therapy have shown good safety
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T-cell immunotherapy has attracted much attention, and safety management has a long way to go.
T-cell immunotherapy has long attracted attention and plays an indispensable role in improving the therapeutic effect, especially for refractory tumors
.

From a theoretical point of view, the vast majority of tumor immunotherapy uses T cells to exert anti-tumor effects, from traditional cytokines and polypeptide drugs to today's immune checkpoint inhibitors (ICIs), chimeric antigen receptors In vivo (CAR) T cell therapy, bispecific antibody (BsAb), etc.
, all indirectly or directly activate human T cells to remove tumor cells.
Today, immunotherapy with the help of T cell activity has opened a new era of tumor immunotherapy, which has also become a new era of tumor immunotherapy.
Important directions for the development of tumor immunity in the future
.

However, due to the potent mechanism of action of T-cell immunotherapy, it often causes massive release of cytokines, leading to multi-system damage in the body, and the occurrence of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS)-like neurological adverse events.
The use has been affected to a certain extent, and it is not a small challenge to manage the safety while ensuring the efficacy
.

Taking CAR-T cell therapy as an example, the incidence of CRS is about 42%-93%, and the neurotoxicity event is about 20.
3%-64%1-4
.

Currently, the management of CRS and ICANS-like neurological adverse events in most patients is mainly through the use of tocilizumab and steroids
.

Immunotherapy-induced CRS5 The current key clinical research safety data of CAR-T cell therapy compares Glofit's unique drug regimen to help reduce the incidence of CRS In the field of non-Hodgkin's lymphoma (NHL) treatment, in addition to CAR-T cell therapy, Another important research direction in tumor therapy mediated by T cells is bispecific antibodies, which can target two different antigen-binding sites: one for tumor antigens and the other for activating cytotoxic cells to exert anti-tumor activity
.

Glofitamab (Glofit for short) is an IgG1-like fully humanized, Fc-segment-silencing, CD20/CD3 bispecific antibody with a unique 2:1 structure.
Activates and targets the immune response against tumor cells, thereby achieving anti-tumor effects
.

In terms of drug safety management, dose escalation and single use of anti-CD20 monoclonal antibodies (such as octuzumab) before infusion can reduce the incidence of CRS6
.

Glofit's molecular structure Glofit's drug mechanism of action Glofit is pretreated with octuzumab to provide better clinical application characteristics: lower levels of cytokine release and effective mitigation of CRS-related toxicity
.

In preclinical studies, the octuzumab-pretreated group had lower levels of cytokine release and a higher percentage of mice that were tumor-free at the end of treatment
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In a phase I clinical study, pretreatment with octuzumab 7 days prior to the first dose of Glofit was able to effectively bind and deplete B cells at the initial stage of treatment, reducing the number of cells in peripheral blood and normal tissues brought about by Glofit-activated T cells immune killing, thereby effectively reducing the risk of CRS6
.

Otuzumab Pretreatment Effectively Reduces Cytokine Release Glofit's Unique Medication Approach A multicenter Phase I study YO42610 (CTR20202232)7 being conducted in China includes patients with R/R DLBCL who have failed two or more prior systemic therapies
.

Otuzumab 1000 mg is pre-treated on day 1 of cycle 1, and then Glofit monotherapy will be administered as a step-up dosing (SUD) intravenous infusion on days 8 and 1 of cycle 1 For 15 days, 2.
5 mg and 10 mg were infused respectively, and 30 mg was infused on the first day of the 2-12 cycle.
The drug was continuously administered for a total of 12 cycles, each cycle of 21 days
.

The structure of Glofit 2:1 can still competitively bind to the CD20 antigen target in the presence of anti-CD20 drugs.
The purpose of SUD administration is also to reduce the risk of CRS, allowing the administration of higher target doses of Glofit
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This study is underway and is expected to benefit more Chinese DLBCL patients
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Glofit's key study design ASH has added new evidence, and many recent developments have confirmed the safety of Glofit.
Glofit monotherapy for R/R NHL CRS mainly occurs in the early stage of treatment, and most of them are grades 1-2.
The 8NP30179 (NCT03075696) study is an ongoing Phase I/II dose escalation/expansion study
.

Early data presented at the 2020 EHA meeting showed that pretreatment with 1000mg octuzumab at a fixed dose (0.
6-25mg) of Glofitamab was effective in reducing CRS
.

This year's ASH meeting updated the data of the study.
The clinical deadline was May 18, 2021.
The study included 183 patients with aggressive lymphoma (DLBCL, transformed follicular lymphoma, mantle cell lymphoma, etc.
) and 75 patients.
In patients with indolent lymphoma (grade 1-3a follicular lymphoma), the median number of lines of therapy was 3 (1-13), and 86% of patients were refractory to prior therapy
.

The extended follow-up indicated that the safety of Glofit monotherapy in R/R NHL was controllable, and no new safety signals were detected: the most common adverse reaction was CRS (58.
9%), mainly grade 1-2 (53.
9%), and Mainly occurred in cycles 1 and 2; there were only 4 ICANS events, all grade 1-2, that resolved by the clinical cutoff date
.

Glofit in combination with R-CHOP in treatment-naïve DLBCL patients with extremely low incidence of CRS without ICANS adverse events Preliminary results of sexual trials showed that Glofit combined with R-CHOP regimen had tolerable safety for R/R NHL and newly-treated DLBCL, all patients could tolerate R-CHOP dose intensity, and the R/R NHL cohort had large CRS events.
Some were grade 1-2, and ICANN-like adverse events were rare, with only 1 case (3.
2%)
.

It is worth mentioning that the first-line DLBCL cohort had a very low probability of CRS and no ICANS adverse events, and only 1 case of grade 1 CRS with fever
.

Glofit in combination with Pola in patients with R/R B-NHL, consistent with a single-agent safety profile (Pola for short) safety, tolerability and efficacy in patients with R/R B-NHL
.

The conference announced the preliminary results of the Glofit+Pola cohort.
A total of 59 patients with R/R DLBCL were included, most of which were high-risk and/or refractory patients
.

At the recommended phase II dose (RP2D), Glofit combined with Pola has a tolerable safety profile and encouraging preliminary efficacy in patients with R/R-DLBCL
.

The most common adverse event was CRS (42.
4%), which occurred mainly after the first dose of Glofit, with the exception of 1 grade 5 CRS*, most of which were grade 1, no grade 3-4 CRS reported, 7 cases (11.
9 %) using tocilizumab for CRS events
.

There was only one grade 1 ICANN adverse event
.

No new safety signals were detected in the Glofit+Pola combination regimen, and the safety was consistent with that of the single drug
.

*This patient is a 73-year-old HGBCL patient with advanced disease and multiple risk factors for CRS, with a history of urosepsis and herpetic stomatitis, and refused further intensive treatment for CRS There is no unexpected toxicity in either monotherapy or combination chemotherapy, and the safety is controllable.
The CRS caused by the use of Glofit is usually grade 1 or 2, and most of them occur during the first infusion of Glofit.
Grade ≥2 CRS events occurred within the first 10 hours of Glofit dosing
.

However, it is currently difficult to predict the risk of CRS in individual patients.
A CRS prediction model was developed based on data from the NP30179 study to predict the incidence of ≥ grade 2 CRS after the first infusion of Glofit to achieve risk-stratified management
.

The model is analyzed and validated by three datasets: (1) The most valuable high-risk risk factors of CRS are identified through the training cohort, and the CRS risk score is finally obtained by combining their tendency to CRS risk with different weights
.

The score is composed of 8 factors: LDH>280U/L, WBC>4.
5*109/L, over 64 years old, cardiac comorbidities, bone marrow infiltration, peripheral blood atypical cells, Ann Arbor stage III or IV, SPD≥3000mm2 suggest a higher risk of CRS
.

The 3 datasets for the prediction model were based on the Glofit initial dose adjustment training cohort (fixed, fractionated doses of 2.
5/10/16 mg, N=196) Results (2) The model validation dataset was initially composed of 51 patients in the RP2D dose cohort Validate model prediction performance
.

(3) Further critical value validation was performed under the key cohort, RP2D dose, to test its final predictive ability, that is, the "complete validation cohort"
.

The low-risk group (CRS risk score <5.
0) accounted for 52% of the complete validation dataset, and patients had only a 5% probability of developing grade ≥2 CRS (NPV=0.
95, SE=0.
03)
.

The model employs a CRS risk score +/- cytokine release level detection that incorporates 8 baseline factors to allow accurate risk classification of ≥ grade 2 CRS on Glofit treatment, enabling CRS risk stratification of patients, adjusting for different risk patients accordingly The monitoring intensity of 11 has improved the management of CRS in patients in clinical practice
.

Big coffee commented that the concept of "bispecific antibody" was first proposed by Professor Song Yuqin in the 1960s.
Although "bispecific T cell engager (BiTE)" drugs have been approved for marketing, those with natural antibody structure It is still in the exploratory stage for dual-antibody drugs to enter a wide range of clinical applications
.

It is reassuring that in recent years there has been increasing interest and attention in the field of hematological tumor therapy for bispecific antibody-mediated T-cell immunotherapy
.

The clinical data of the CD20/CD3 bispecific antibody Glofitamab announced at this year's ASH meeting in the treatment of aggressive lymphoma are very encouraging, and the safety has been significantly improved compared to similar therapies
.

Tracing the source, starting from the mechanism of action of these drugs, pretreatment with anti-CD20 monoclonal antibodies (such as octuzumab) and dose escalation in the first cycle before Glofit infusion can effectively reduce the occurrence of CRS events
.

In addition, the risk prediction model for CRS events of grade 2 and above after patients receiving treatment has also been preliminary and reliable exploration, which provides effective guidance for the future clinical practice and safe application of such drugs.
We look forward to Glofit in China as soon as possible.
With the release of more safety-related data in the future, it can further escort patients with relapsed or refractory lymphoma
.

Professor Zhang Huilai's CD20/CD3 bispecific antibody Glofitamab monotherapy is gaining momentum in the NHL field, and a number of monotherapy or combination therapy options are being explored.
Whether it's a single drug or a combination therapy, preliminary results have shown that Glofitamab It has excellent performance in improving remission rate and prolonging remission duration, and has a good safety profile
.

A study of the CRS risk prediction model based on the NP30179 study announced at the ASH meeting clarified the main risk factors for the occurrence of grade 2 and above CRS events during Glofit treatment.
This CRS risk prediction score can effectively guide different risks to a certain extent.
The intensity of CRS monitoring in patients with different grades has the potential to help clinically establish a more standard and complete CRS management method for lymphoma patients
.

Judging from the latest progress of ASH, the future application of Glofit is very promising.
The research data includes a variety of aggressive or indolent non-Hodgkin lymphomas.
Provide more safe and effective treatment options for cancer patients
.

Abstract 2479.
10.
2021 ASH.
Abstract 525.
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2021 ASH.
Abstract 1459.
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