The 63rd Annual Meeting of the American Society of Hematology (ASH), the world's largest international event in hematology, was held in Atlanta, USA, from December 11 to 14, 2021. The publication of a number of blockbuster studies and the latest results at the ASH Annual Meeting has greatly promoted the development of the field of hematology and provided academic exchange opportunities for promoting the diagnosis and treatment of hematological diseases of clinicians.
At the right time, closely following the international hot spots, focusing on diffuse large B-cell lymphoma (DLBCL) and the frontiers of immunotherapy, Medical Pulse sincerely invited Professor Song Yuqin of Peking University Cancer Hospital and Professor Zhang Huilai of Tianjin Medical University Cancer Hospital to share the development ideas of T cell therapy, the latest clinical progress and unique safety advantages of bispecific antibody Glofitamab (referred to as Global) for readers.
Highlights:
- T cell immunotherapy is an important direction for the future development of tumor immunity, and safety management needs to be paid attention to under the premise of ensuring efficacy.
- Glofit provides better clinical properties through otolizumab pretreatment (Gpt): lower cytokine release levels and effective reduction of cytokine release syndrome (CRS)-related toxicity.
- Ash adds a number of new evidences, glofit monotherapy and combination therapy have demonstrated good safety.
T-cell immunotherapy has attracted much attention, and safety management has a long way to go
T-cell immunotherapy has long been a concern and plays an indispensable role in improving the effectiveness of treatment, especially for refractory tumors. From a theoretical point of view, the vast majority of tumor immunotherapy is through T cells to play an anti-tumor effect, from the traditional cytokines, polypeptide drugs, and then today's immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T cell therapy, bispecific antibodies (BsAb), etc., are indirect or direct activation of human T cells to clear tumor cells, and now with the help of T cell activity immunotherapy has opened a new era of tumor immunotherapy, It has also become an important direction for the development of tumor immunity in the future.
However, due to the strong mechanism of action of T cell immunotherapy, it often causes a large release of cytokines to cause multi-system damage to the body, and the occurrence of CRS and immune effector cell-related neurotoxic syndrome (ICANS)-like neurological adverse events has affected the use of T cell immunotherapy to a certain extent, and it is no small challenge to do a good job in safety management while ensuring 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, CRS and ICANS-like neurological events are managed primarily through the use of tocilizumab and steroids, among others.
Immunotherapy induces CRS5
Current safety data comparison of key clinical studies of major CAR-T cell therapies
Glofit's unique medication method helps reduce the incidence of CRS
In the field of non-Hodgkin lymphoma (NHL) treatment, in addition to CAR-T cell therapy, another important research direction for mediating T cell tumor therapy is bispecific antibodies, which can target two different antigen binding sites: one targets tumor antigens, and the other is used to activate cytotoxic cells and exert antitumor activity.
Glofitamab (Glofitamab) is an IgG1-like, fully humanized, Fc-segment silencing treatment, CD20/CD3 bispecific antibody with a unique 2:1 structure, which binds to B cell CD20 and T cell CD3 at the same time, inducing T cell activation and immune response against tumor cells, thereby achieving anti-tumor effects. In terms of the safety management of this drug, dose-increasing administration and a single use of anti-CD20 monoclonal antibody (e.g., otolizumab) prior to infusion can reduce the incidence of CRS6.
Molecular structure of Glofit
Glofit's mechanism of action of the drug
Glofit provides better clinical properties through otolizumab pretreatment: lower cytokine release levels and effective reduction of CRS-related toxicity.
- In preclinical studies, cytokine release levels were lower in the ottularizumab pretreatment group and a higher proportion of mice that survived without tumors at the end of treatment.
- In phase I clinical studies, otolizumab pretreatment with otolizumab 7 days before the first administration of Glofit was able to effectively bind and deplete B cells at the beginning of treatment, reducing the cellular immune killing caused by Glofit-activated T cells in peripheral blood and normal tissues, thereby effectively reducing the risk of CRS6.
Otolizumab pretreatment effectively reduces cytokine release
- Glofit's unique way of using medicines
A multicenter Phase I study, YO42610 (CTR20202232)7, which is being conducted in China, included patients with R/R DLBCL who had previously failed two-line or more systemic therapy. 1000 mg of otolizumab is pretreated on day 1 of the first cycle, followed by Grufit monotherapy in intravenous infusion by dose-increasing (Step-Up Dosing, SUD), with 2.5 mg and 10 mg on days 8 and 15 of cycle 1, and 30 mg on day 1 of cycle 2-12, respectively, for a total of 12 consecutive cycles of 21 days per cycle. Glofit 2:1 has structures that competitively bind to CD20 antigen targets in the presence of anti-CD20 drugs, and the purpose of SUD administration is to reduce the risk of CRS and allow higher target doses ofGlofit to be administered. The study is ongoing and is expected to benefit more Chinese DLBCL patients.
Glofit key study design
ASH has added new certificates, and several recent developments confirm the safety of Global
- GLOFit monotherapy for R/R NHL CRS occurs mainly in the early stages of treatment and is mostly grade 1-28
The NP30179 (NCT03075696) study is an ongoing Phase I/II dose escalation/extension study. Early data presented at the 2020 EHA conference showed that in the fixed dose (0.6-25 mg) Glefitamab administration group, 1000 mg of otolizumab pretreatment was effective in reducing CRS. This year's ASH conference updated the study's data, and as of May 18, 2021, the study included a total of 183 patients with invasive lymphoma (DLBCL, transformed follicular lymphoma, sleeve cell lymphoma, etc.) and 75 patients with indolent lymphoma (grade 1-3a follicular lymphoma), with a median treatment line of 3 (1-13), and 86% of patients were refractory to previous treatment. Extended follow-up suggests that Glofit monotherapy with R/R NHL is safe and no new safety signals have been detected: the most common adverse reaction was CRS (58.9%), mainly grade 1-2 (53.9%), and occurred mainly in cycles 1 and 2; only 4 ICANS events, all grades 1-2, were resolved by the clinical deadline.
- The Glofit plus R-CHOP regimen had a very low incidence of CRS in patients treated with new-time DLBCL and no ICANS adverse events9
The NP40126 study (NCT03467373) is an ongoing Phase 1b study, preliminary results from R/R NHL dose escalation and first-line DLBCL safety trials showing that Glofit plus R-CHOP regimen has a tolerable safety profile for R/R NHL and primary DLBCL, all patients can tolerate R-CHOP dose intensity, most crS events in the R/R NHL cohort are of grade 1-2, and ICANS-like adverse events are rare, Only 1 case (3.2%). It is worth mentioning that the probability of CRS occurring in the first-line DLBCL cohort is extremely low and there are no ICANS adverse events, and only one case of grade 1 CRS is accompanied by fever.
- Glofit in combination with the Pola regimen for patients with R/R B-NHL is consistent with the safety profile of a single drug10
The NP39488 study is an ongoing, Phase Ib/II dose escalation and extended study designed to evaluate the safety, tolerability, and efficacy of Glofitamab in combination with atenilizul or Polazumab or Polazumab vedotin (Pola) in patients with R/R B-NHL. The preliminary results of the Global+Pola cohort were presented at this conference, which included a total of 59 patients with R/R DLBCL, most of whom were high-risk and/or refractory to previous treatment. At the recommended phase II dose (RP2D), Glofit in combination with Pola in patients with R/R-DLBCL had a tolerable safety and encouraging initial efficacy. The most common adverse event was CRS (42.4%), which occurred mainly after the first administration of Glofit, except for 1 case with a grade 5 CRS*, most CRS was grade 1, no grade 3-4 CRS was reported, and 7 (11.9%) with tocilizumab was used to treat CRS events. Only one case had a grade 1 ICANS adverse event. The joint Glofit+Pola protocol did not detect new safety signals, and the safety was consistent with that of a single drug.
*The patient was a 73-year-old HGBCL patient with advanced disease and multiple RISK factors for CRS, with a history of urothritis and herpetic stomatitis, and was denied further intensive treatment of CRS
Many of the above research advances suggest thatGlofit has a good safety profile, neither monotherapy nor combination chemotherapy has the expected toxicity, the safety is controllable, the CRS caused by the use ofGlofit is usually grade 1 or 2, and most of them occur during the first infusion ofglofit, and most ≥ grade 2 CRS events occur within 10 hours of Glofit administration. However, it is currently difficult to predict the risk of CRS in individual patients, and a CRS prediction model developed based on NP30179 research data predicts the incidence of grade 2 CRS ≥ after the first infusion of Global to achieve risk stratification management.
The model was analyzed and validated by three datasets: (1) the high-risk factors of the most valuable CRS were identified through the training cohort, combined with the different levels and weights of the CRS risks they tended to, and the CRS risk score was finally obtained. The score consisted of eight factors: LDH>280U/L, WBC >4.5*109/L, >64 years, cardiac comorbidities, bone marrow infiltrates, atypical peripheral blood cells, Ann Arbor stage III or IV, SPD≥3000mm2 all suggested a higher risk of CRS.
3 datasets of the predictive model
Adjust the results of the training cohort (fixed, divided doses of 2.5/10/16 mg, N=196) according to the initial dose of Global
(2) The model validation dataset consisting of 51 patients in the RP2D dose cohort preliminarily verified the model prediction performance.
(3) Further critical value verification at the critical cohort, RP2D dose, to test its final predictive ability, i.e. the "full validation cohort". Among them, the low-risk group (CRS risk score <5.0) accounted for 52% of the complete validation dataset, and only 5% of patients had a ≥ grade 2 CRS (NPV=0.95, SE=0.03).
The model uses CRS risk score +/- cytokine release level detection with 8 baseline factors to allow accurate risk classification of ≥-level CRS treated withGlofit, thereby achieving CRS risk stratification in patients, adjusting the monitoring intensity of patients at different risks accordingly11, and improving crS management in clinical practice.
Big coffee reviews
Professor Song Yuqin
In the 1960s, the concept of "bispecific antibodies" has been proposed for the first time, and although there are currently "bispecific T cell adapters (BiTE)" drugs approved for marketing, diantine drugs with natural antibody structures are still in the exploratory stage when they enter a wide range of clinical applications. It is gratifying 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 on the treatment of invasive lymphoma by the CD20/CD3 bispecific antibody Glofitamab, published at this year's ASH conference, are encouraging, and the safety has improved significantly compared with similar therapies. Tracing back to the source, starting from the mechanism of action of this class of drugs, anti-CD20 monoclonal antibody (such as otolizumab) pretreatment and first cycle dose increase beforeGlofit infusion can effectively reduce the occurrence of CRS events. In addition, there has been a preliminary reliable exploration of the risk prediction model for crS events occurring after patients receive treatment, which provides effective guidance for the future entry of such drugs into clinical practice and safe application, and it is expected thatGlofit can be listed in China as soon as possible, and with the release of more safety-related data in the future, it can further escort patients with relapsed or refractory lymphoma.
Professor Zhang Huilai
CD20/CD3 bispecific antibody Glofitamab monotherapy is poised in the NHL field, and multiple single-agent or combination therapy regimens are being explored, whether single-agent or combination, and preliminary results have shown thatGlofit has performed well in improving remission rates and prolonging the duration of remission, and has good safety. A study based on the NP30179 crS risk prediction model presented at the ASH conference clarified the main risk factors for the occurrence of CRS events of grade 2 and above during The treatment of Global, and this CRS risk prediction score can effectively guide the CRS monitoring intensity of patients with different risk levels to a certain extent, and has the potential to help clinically establish a more standard and perfect CRS management method for lymphoma patients. Judging from the latest progress of ASH, glofit's future application prospects are very broad, and the research data includes a variety of invasive or inert non-Hodgkin lymphoma, and it is expected that more confirmatory clinical research results will be released in the future, in order to provide more safe and effective treatment options for patients with B-cell lymphoma.
Professor Song Yuqin
- Deputy Director, Chief Physician and Doctoral Supervisor of the Department of Lymphoma, Peking University Cancer Hospital
- Director of the Chinese Society of Clinical Oncology (CSCO).
- Secretary General of the Anti-Lymphoma Alliance of the Chinese Society of Clinical Oncology (CSCO).
- Chairman of the Lymphatic Hematology And Tumor Professional Committee of Beijing Anti-Cancer Association
- Vice Chairman of the Lymphohematology Oncology Professional Committee of the Chinese Geriatric Oncology Society
- Vice Chairman of the Lymphoma Professional Committee of the Chinese Geriatric Health Care Association
- Member of the Standing Committee and Secretary of the Oncology Committee of the Beijing Medical Association
Zhang Huilai Professor
- Doctor of Oncology, Chief Physician, Doctoral Supervisor
- He is currently the director of the Department of Lymphoma Internal Medicine, Cancer Hospital of Tianjin Medical University
- His main research interests are molecular diagnosis and individualized treatment of malignant lymphoma
- Vice Chairman of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association
- Member of the Standing Committee of the Lymphoma Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
- Vice Chairman of the Internal Oncology Branch of the Chinese Medical Promotion Association
- Member of the Standing Committee of the Oncology And Cardiology Committee of the Chinese Society of Clinical Oncology (CSCO).
- Member of the Lymphoma Group of the Oncology Branch of the Chinese Medical Association
- Member of the Integrated Oncology Cardiology Committee of the Chinese Anti-Cancer Association
- Chairman of the Lymphoma Professional Committee of Tianjin Anti-Cancer Association
- Vice Chairman of Tianjin Hematology Quality Control Center
- Vice President of Hematologist Branch of Tianjin Medical Doctor Association
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6.Jing Zhang, et al. Antib Ther. 2020 May 30;3（2）:126-145.
7.http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml.(Query date: December 27, 2021)
8.2021 ASH. Abstract 2478.
9.2021 ASH. Abstract 2479.
10.2021 ASH. Abstract 525.
11.2021 ASH. Abstract 1459.