Early toxicity and clinical outcomes after chimeric antigen receptor T-cell (CAR-T) therapy for lymphoma
Jonathan E. BrammerZachary BraunsteinAashish KatapadiKyle PorterMichael BiersmithAvirup GuhaSumithira VasuVedat YildizSakima A. SmithBenjamin BuckDevin HaddadRichard J. GuminaBasem M. WilliamSam PenzaAyman SaadNathan DenlingerAjay VallakatiRagavendra R. BaligaRaymond L. BenzaPhilip F. BinkleyLai WeiMason MocarskiSteven M. DevineSamantha JaglowskiDaniel Addison
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Background Chimeric antigen receptor T-cell (CAR-T) infusion is associated with early toxicity. Yet, whether early toxicity development holds ramifications for long-term outcomes is unknown. Methods From a large cohort of consecutive adult patients treated with CAR-T therapies for relapsed or refractory lymphomas from 2016 to 2019, we assessed progression-free survival (PFS), by toxicity development (cytokine release syndrome (CRS), neurotoxicity, or cardiotoxicity]. We also assessed the relationship of toxicity development to objective disease response, and overall survival (OS). Multivariable regression was utilized to evaluate relationships between standard clinical and laboratory measures and disease outcomes. Differences in outcomes, by toxicity status, were also assessed via 30-day landmark analysis. Furthermore, we assessed the effects of early anti-CRS toxicity therapy use (at ≤grade 2 toxicity) on maximum toxicity grade observed, and long-term disease outcomes (PFS and OS). Results Overall, from 102 CAR-T-treated patients, 90 were identified as treated with single-agent therapy, of which 88.9% developed toxicity (80 CRS, 41 neurotoxicity, and 17 cardiotoxicity), including 28.9% with high-grade (≥3) events. The most common manifestations were hypotension at 96.6% and fever at 94.8%. Among patients with cardiac events, there was a non-significant trend toward a higher prevalence of concurrent or preceding high-grade (≥3) CRS. 50.0% required tocilizumab or corticosteroids. The median time to toxicity was 3 days; high grade CRS development was associated with cardiac and neurotoxicity. In multivariable regression, accounting for disease severity and traditional predictors of disease response, moderate (maximum grade 2) CRS development was associated with higher complete response at 1 year (HR: 2.34; p=0.07), and longer PFS (HR: 0.41; p=0.02, in landmark analysis), and OS (HR: 0.43; p=0.03). Among those with CRS, relative blood pressure (HR: 2.25; p=0.004), respectively, also associated with improved PFS. There was no difference in disease outcomes, or maximum toxicity grade (CRS, neurotoxicity, or cardiotoxicity) observed, based on the presence or absence of the use of early CRS-directed therapies. Conclusions Among adult lymphoma patients, moderate toxicity manifest as grade 2 CRS after CAR-T infusion may associate with favorable clinical outcomes. Further studies are needed to confirm these findings.Keywords:
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がん特異的抗体の抗原認識部位とCD28等の共刺激分子及びCD3ζとの融合体であるCAR（chimeric antigen receptor）を発現するCAR-T細胞は，がん特異的抗原を認識して活性化し，がん細胞を傷害する．CD19を標的としたCAR-T細胞のB細胞性血液がんに対する効果は驚異的であり，今までは治すことができなかった多くの患者を治すことができる．抗IL（interleukin）-6レセプター抗体を用いてサイトカイン放出症候群のコントロールをすれば，比較的安全に施行できるということがわかるにつれ，CD19 CAR-T細胞治療を実施する施設はどんどん増加しており，もはや血液内科においてはCAR-T細胞療法は一般的な選択肢の一つとなった．次にターゲットとなる疾患としては多発性骨髄腫（multiple myeloma：MM）が有力で，すでにB細胞成熟抗原（B-cell maturation antigen：BCMA）を標的としたCAR-T細胞の有効性が報告されている．我々も活性化インテグリンβ7に特異的なCAR-T細胞がMMに有効である可能性を示し，その臨床開発を進めている．
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Multiple myeloma remains the second most common hematologic malignancy, and relapse rates are high, with refractory disease common with each relapse. Chimeric antigen receptor (CAR)–modified T cells are a promising new treatment, and at JADPRO Live Virtual 2021, presenters compared pivotal trials in CAR T-cell therapy for multiple myeloma, discussed how to recognize and manage common toxicities after CAR T-cell infusion, and reviewed pre-CAR-T consultation and post-CAR-T management.
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Remarkable improvement relative to traditional approaches in the treatment of hematological malignancies by chimeric antigen receptor (CAR) T-cell therapy has promoted sequential approvals of eight commercial CAR T products within last 5 years. Although CAR T cells' productization is now rapidly boosting their extensive clinical application in real-world patients, the limitation of their clinical efficacy and related toxicities inspire further optimization of CAR structure and substantial development of innovative trials in various scenarios. Herein, we first summarized the current status and major progress in CAR T therapy for hematological malignancies, then described crucial factors which possibly compromise the clinical efficacies of CAR T cells, such as CAR T cell exhaustion and loss of antigen, and finally, we discussed the potential optimization strategies to tackle the challenges in the field of CAR T therapy.
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キメラ抗原受容体(Chimeric Antigen Receptor,CAR)-T細胞療法は遺伝子改変T細胞による養子免疫療法の一つであり,急性リンパ性白血病,悪性リンパ腫,慢性リンパ性白血病などのB細胞性腫瘍や多発性骨髄腫に対する新規治療法として近年非常に注目されている.CD19抗原を標的としたCAR-T細胞による国際共同第2相試験において,難治性B細胞性腫瘍に対して高率な寛解導入効果が示された.CAR-T細胞は短期間で調製でき,T細胞が持つT細胞受容体より高い親和性をもった抗体を抗原受容体として利用したことが成功に寄与した.また抗体を抗原受容体とすることでT細胞のHLA拘束性を考慮する必要がない.CARの構造は細胞外ドメインとし抗体のFab部分と,細胞内ドメインとしてT細胞のシグナルドメインから成る.T細胞の活性化や機能増強,体内での長期生存能を付与するために細胞内ドメインにはさまざまな工夫が施されてきた.ただし治療後にサイトカイン放出症候群などの重篤な副作用が高頻度に起こりうる他,長期的には一部に再発も認められ,今後解決すべき課題も残されている.
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Chimeric antigen receptor (CAR)-T cell therapy is a fast-emerging treatment for several types of cancers and has several applications beyond oncology. It is a new emerging treatment targeting for a broad range of cancers. The objective of this review is to provide the trending information on CAR-T cell therapies, basic principles involved in the CAR-T cell therapy, structure of CAR-T cell, and mainly various clinical applications in the field of oncology as well as beyond oncology, and major side effects of CAR-T cell therapy, methods to overcome the risk factors and to minimize the cost. Although, the cost of treatment is enormous, cost effectiveness can be done by understanding the demand informed by tertiary healthcare centers to manufacture units for decreasing the complexity of the procedure. But this therapy is associated with few-toxicities. Monitoring these toxicities and minimizing the severity is the main future prospective of CAR-T cell therapy. The next stage in developing CAR-T cell therapy for malignancies is to limit exposure to specific cells because future CAR-T cells can target different antigens. Due to the increasing number of potential targets for CAR-T cell therapy, this approach’s tremendous success in treating cancer may also be used to the treatment of other diseases.
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Chimeric antigen receptor (CAR) T cell therapy has significantly improved the outlook for patients with certain types of poor-risk lymphoma. Despite these advances, a majority of patients undergoing CAR T therapy will suffer progression or relapse of disease, and toxicity remains a concern. Additionally, the patients and disease subtypes that are most likely to benefit from CAR T have yet to be fully defined. Many ongoing trials are exploring novel CAR T approaches to address these concerns. In this review, we highlight some of the primary strategies and relevant studies aimed at improving the utility of CAR T therapy in lymphoma.
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The number of cases of chimeric antigen receptor T (CAR-T) cell therapy has been rapidly increasing in Japan since Tisagenlecleucel was approved in March 2019, and clinical experience with CAR-T therapy for CD19 has demonstrated that the therapy can be performed safely than initially expected. The current challenge for CAR-T therapy is insufficient response, as about 50% of patients who receive CD19 CAR-T therapy eventually relapse or become refractory. The causes can be generally classified as CAR-T cell exhaustion and lack of sufficient effector function, loss of the target antigen, and extremely rapid tumor growth, and countermeasures are being investigated and developed for each of these causes. Additionally, the development of novel CAR-T therapies is also desired. In this article, we discuss the current status and future prospects of these issues, including our own efforts.
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Recent advances with chimeric antigen receptor T-cell (CAR-T) therapy are changing the current landscape of poor-prognosis relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Pivotal trials leading to the FDA approval of three CD19 CAR-T cells, namely, Yescarta®, Kymriah®, and Breyanzi®, demonstrated complete response rates of 40-60%, with a significant subset of patients achieving long-term disease remission, and real-world studies confirm these data. In Japan, CAR-T therapy was approved for R/R DLBCL in 2019 and for R/R follicular lymphoma in 2022. However, guidelines are not clear on which CAR-T agents should be indicated for which patients and at which timing, and currently, institutions decide and operate according to their criteria. To optimize CAR-T therapy under the best conditions, the treatment strategy must be decided with the referring institution in terms of T-cell fitness and tumor volume. Therefore, institutional collaboration to monitor long-term adverse events after CAR-T therapy is important.
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Summary Chimeric antigen receptor (CAR) T cell therapies offer a promising new therapeutic option for treating B cell malignancies, for instance relapsed or refractory diffuse large B cell lymphoma (DLBCL). However, patient access to this type of cellular immunotherapy may be limited due to systemic barriers even in wealthy Western countries. In Austria, the CAR T eligible DLBCL population is estimated to encompass approximately 56 patients based on the criteria applied for CAR T registrational trials. However, less than 40% of these DLBCL patients eligible for commercial standard-of-care CAR T cell therapy were finally treated with CAR T cell therapy in 2021 based on our analysis. This report discusses potential barriers that may impede current patient access to CAR T cell therapy and provides recommendations for systemic solutions to address these barriers and improve the CAR T access situation in Austria.
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Chimeric antigen receptor T-cell (CAR-T) therapy is a new innovative cancer treatment. In recent years, many clinical studies have demonstrated its efficacy in the treatment of DLBCL. Compared to many existing cancer treatments, CAR-T therapy offers many advantages. For example, unique specificity and excellent efficacy in patients with refractory and recurrent tumors. This article focuses on the application of CAR-T in the treatment of DLBCL and analyzes the advantages and disadvantages of this therapy from multiple perspectives. The advantages of CAR-T therapy are discussed in three aspects: CAR-T for relapsed and chemotherapy-resistant patients, CAR-T cell’s distinctive specificity and ideal treatment outcome. Then, the three most representative limitations of CAR-T therapy are analyzed in this article: antigen escape, antigen-positive relapse, and toxicities. Finally, the article points out the promising future of CAR-T therapy.
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