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Transformed Lymphoma Is Associated with a Favorable Response to CAR-T-Cell Treatment in DLBCL Patients

轉(zhuǎn)化淋巴瘤與 DLBCL 患者對(duì) CAR-T 細(xì)胞治療的良好反應(yīng)有關(guān)

The clinical features predicting favorable outcomes after CAR-T-cell treatment are a matter of ongoing debate. This study aimed to evaluate the potential importance of lymphoma subtypes regarding prognostic significance, mainly to compare transformed versus de novo DLBCL. We found that patients with transformed/secondary lymphoma have a decisively more favorable course after CAR-T-cell therapy than patients with de novo lymphoma.

預(yù)測(cè) CAR-T 細(xì)胞治療后有利結(jié)果的臨床特征是一個(gè)持續(xù)爭(zhēng)論的問題。本研究旨在評(píng)估淋巴瘤亞型對(duì)預(yù)后意義的潛在重要性，主要是比較轉(zhuǎn)化與新生 DLBCL。我們發(fā)現(xiàn)轉(zhuǎn)化/繼發(fā)性淋巴瘤患者在接受 CAR-T 細(xì)胞治療后的病程明顯優(yōu)于新發(fā)淋巴瘤患者。

三角細(xì)胞搖瓶

Currently, chimeric antigen receptor T-cell therapy (CAR-T) is in the process of being introduced in an increasing number of centers for patients with refractory or relapsed aggressive B-cell lymphoid malignancies. So far, approved CAR-T-cell products for such patients rely on autologous genetically engineered T-lymphocytes, which express a chimeric antigen receptor (CAR) against the pan-B-cell CD19 antigen [1,2,3,4,5,6,7]. The basic anatomy of a CAR structure consists of an antigen-recognition domain, usually a single-chain variable fragment derived from a monoclonal antibody targeting the selected antigen (i.e., CD19); a hinge (usually derived from CD8 or Ig4 molecules) that links the recognition site to the transmembrane domain, which bridges the membrane; and finally, the intracellular domain that typically contains the CD3z chain critical for T-cell receptor signaling [8]. T-cell engineering started in 1990 with the development of the first generation of CAR-T cells in 1993; however, their clinical effectiveness was reduced due to their short persistence. After the introduction of a co-stimulatory domain in 1998, second-generation CARs were introduced in 2003. They were built to target CD19, and their discovery led to the first success in the treatment of aggressive lymphatic malignancies in 2011. The CD19 antigen is a transmembrane glycoprotein involved in regulating B-lymphocyte activation through humoral signaling [8]. CD19 is an ideal target that is ubiquitously expressed in B-lymphocytes, and its expression is maintained during lymphoid B-cell maturation and, importantly, neoplastic transformation [9].

Based on the JULIET trial [2,6,10,11], tisagenlecleucel (tisa-cel) was approved by the European Medicines Agency (EMA) in 2018 for refractory/relapsed (r/r) diffuse large B-cell lymphoma (DLBCL) after at least two previous treatment lines as well as for r/r B-cell acute lymphoblastic leukemia (B-ALL) in children and young adults up to 25 years of age with failure or relapse after two previous therapies or following allogeneic hematopoietic stem-cell transplantation (HSCT). Tisa-cel is a second-generation CAR-T utilizing 4-1BB as a co-stimulatory domain, which was developed by the investigators of the University of Pennsylvania in collaboration with Novartis [2,6]. Axicabtagene ciloleucel (axi-cel) is a second CAR-T-cell product, which the EMA authorized in 2018 for r/r DLBCL and primary mediastinal large B-cell lymphoma (PMBCL) after at least two lines of therapy [3]. It is a second-generation CAR-T utilizing a CD28 co-stimulatory domain. It was initially developed by the investigators of the National Cancer Institute (NCI). Currently, the construct is being developed by Kite Pharma, Gilead Sciences, and Daiichi Sankyo [3]. Lisocabtagene maraleucel (liso-cel) is currently available for relapsed/refractory DLBCL, PMBCL, follicular lymphoma Grade 3B, and mantle cell lymphoma (MCL) and is in the process of obtaining market authorization [4].

Despite the rapidly increasing number of clinical reports, uncertainty remains regarding the factors that impact clinical outcomes after CAR-T-cell treatment [4,5,6,12,13,14,15]. In particular, it remains unclear whether distinct lymphoma subtypes may differ in their response to CAR-T-cell treatment [1,6,7,16,17,18]. For example, a recent report suggested that patients with a history of follicular lymphoma had a better progression-free course than patients with DLBCL [16]. In addition, the TRANSCEND study reported similar findings [4]. Consequently, we investigated clinical and laboratory parameters in a cohort of subsequent patients with lymphoid malignancies for their prognostic significance, focusing on elucidating the impact of transformed (or secondary) versus de novo (or primary) DLBCL histology.

血清培養(yǎng)基瓶

目前，嵌合抗原受體 T 細(xì)胞療法 (CAR-T) 正在越來越多的中心引入，用于治療難治性或復(fù)發(fā)性侵襲性 B 細(xì)胞淋巴惡性腫瘤患者。迄今為止，已批準(zhǔn)用于此類患者的 CAR-T 細(xì)胞產(chǎn)品依賴于自體基因工程 T 淋巴細(xì)胞，這些 T 淋巴細(xì)胞表達(dá)針對(duì)泛 B 細(xì)胞 CD19 抗原的嵌合抗原受體 (CAR) [ 1 , 2 , 3 , 4 , 5 , 6 , 7]。CAR 結(jié)構(gòu)的基本解剖結(jié)構(gòu)包括一個(gè)抗原識(shí)別結(jié)構(gòu)域，通常是一個(gè)單鏈可變片段，來源于針對(duì)選定抗原（即 CD19）的單克隆抗體；一個(gè)鉸鏈（通常來自 CD8 或 Ig4 分子），將識(shí)別位點(diǎn)連接到跨膜結(jié)構(gòu)域，跨膜結(jié)構(gòu)域橋接膜；最后，通常包含對(duì) T 細(xì)胞受體信號(hào)傳導(dǎo)至關(guān)重要的 CD3z 鏈的細(xì)胞內(nèi)結(jié)構(gòu)域 [ 8]。T細(xì)胞工程始于1990年，1993年開發(fā)出第一代CAR-T細(xì)胞；然而，由于它們的持續(xù)時(shí)間短，它們的臨床有效性降低了。1998 年引入共刺激結(jié)構(gòu)域后，2003 年引入了第二代 CAR。它們是針對(duì) CD19 構(gòu)建的，它們的發(fā)現(xiàn)導(dǎo)致 2011 年在治療侵襲性淋巴惡性腫瘤方面取得了第一次成功。CD19 抗原是一種跨膜糖蛋白，參與通過體液信號(hào)傳導(dǎo)調(diào)節(jié) B 淋巴細(xì)胞活化 [ 8 ]。CD19 是一種理想的靶標(biāo)，在 B 淋巴細(xì)胞中普遍表達(dá)，它的表達(dá)在淋巴 B 細(xì)胞成熟過程中得到維持，重要的是，在腫瘤轉(zhuǎn)化過程中 [ 9 ]。

基于JULIET試驗(yàn)[ 2,6,10,11 ] ， tisagenlecleucel （ tisa - cel）于2018年獲歐洲藥品管理局（EMA）批準(zhǔn)用于難治/復(fù)發(fā)（r / r）彌漫性大B細(xì)胞淋巴瘤（DLBCL） ) 在至少兩個(gè)先前的治療線之后以及對(duì)于r / rB 細(xì)胞急性淋巴細(xì)胞白血病 (B-ALL) 在兒童和 25 歲以下的年輕人中，在兩次先前的治療或同種異體造血干細(xì)胞移植 (HSCT) 后失敗或復(fù)發(fā)。Tisa-cel 是利用 4-1BB 作為共刺激域的第二代 CAR-T，由賓夕法尼亞大學(xué)的研究人員與諾華公司合作開發(fā) [ 2 , 6 ]。Axicabtagene ciloleucel (axi-cel) 是第二款 CAR-T 細(xì)胞產(chǎn)品，EMA 于 2018 年批準(zhǔn)該產(chǎn)品用于r / r DLBCL 和原發(fā)性縱隔大 B 細(xì)胞淋巴瘤 (PMBCL) 在至少兩線治療后 [ 3]。它是利用 CD28 共刺激域的第二代 CAR-T。它最初是由美國(guó)國(guó)家癌癥研究所 (NCI) 的研究人員開發(fā)的。目前，該結(jié)構(gòu)由 Kite Pharma、Gilead Sciences 和 Daiichi Sankyo [ 3 ] 開發(fā)。Lisocabtagene maraleucel（liso-cel）目前可用于復(fù)發(fā)/難治性DLBCL、PMBCL、濾泡性淋巴瘤3B級(jí)和套細(xì)胞淋巴瘤（MCL），并且正在獲得市場(chǎng)授權(quán)[ 4 ]。

細(xì)胞培養(yǎng)瓶

盡管臨床報(bào)告數(shù)量迅速增加，但影響 CAR-T 細(xì)胞治療后臨床結(jié)果的因素仍存在不確定性 [ 4 , 5 , 6 , 12 , 13 , 14 , 15 ]。特別是，尚不清楚不同的淋巴瘤亞型在對(duì) CAR-T 細(xì)胞治療的反應(yīng)方面是否可能不同 [ 1 , 6 , 7 , 16 , 17 , 18 ]。例如，最近的一份報(bào)告表明，有濾泡性淋巴瘤病史的患者比 DLBCL 患者有更好的無進(jìn)展病程 [ 16]。此外，TRANSCEND 研究報(bào)告了類似的發(fā)現(xiàn) [ 4 ]。因此，我們調(diào)查了一組后續(xù)淋巴惡性腫瘤患者的臨床和實(shí)驗(yàn)室參數(shù)對(duì)預(yù)后的意義，重點(diǎn)是闡明轉(zhuǎn)化（或繼發(fā)性）與從頭（或原發(fā)性）DLBCL 組織學(xué)的影響。

Our data suggest that transformed/secondary lymphoma is associated with a more favorable outcome after CAR-T-cell therapy compared to de novo/primary lymphoma. However, larger studies may be needed to address this question ultimately and, thereby, to identify those patients who would benefit the most from CAR-T-cell therapy.

我們的數(shù)據(jù)表明，與新發(fā)/原發(fā)性淋巴瘤相比，轉(zhuǎn)化/繼發(fā)性淋巴瘤與 CAR-T 細(xì)胞治療后更有利的結(jié)果相關(guān)。然而，可能需要更大規(guī)模的研究來最終解決這個(gè)問題，從而確定那些將從 CAR-T 細(xì)胞治療中獲益最多的患者。

關(guān)鍵詞：CAR-T-cell therapy,diffuse large B-cell lymphoma (DLBCL),secondary DLBCL; prognosis,relapse,CAR-T細(xì)胞療法,彌漫性大 B 細(xì)胞淋巴瘤（DLBCL）,二級(jí)DLBCL,預(yù)后,復(fù)發(fā)

來源：MDPI https://www.mdpi.com/2072-6694/13/23/6073/htm