Is CAR-T Cell Immunotherapy a Good Strategy for T-Cell Acute Lymphoblastic Leukemia?

Lin Yang1,2,3*
1The Cyrus Tang Hematology Center, Soochow University, China
2Collaborative Innovation Center of Hematology, Soochow University, China
3Suzhou Cancer Immunotherapy and Diagnosis Engineering Center, China

*Corresponding author: Lin Yang, The Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Suzhou Cancer Immunotherapy and Diagnosis Engineering Center, Soochow University, Shi Zi Street, 21500-China, China

Published: 29 Dec, 2016
Cite this article as: Yang L. Is CAR-T Cell Immunotherapy a Good Strategy for T-Cell Acute Lymphoblastic Leukemia?. Clin Oncol. 2016; 1: 1169.


T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive hematologic cancer that arises from the malignant transformation of T-cell progenitorsand occurs in about 15% of pediatric and 25% of adult ALL cases. However, unlike B cell derived B-ALL in which the chimeric antigen receptor modified T cells (CAR-T cells) have been proven clinically successful in treating refractory, relapsed patient settings, there is few report for CAR-T cell therapy in T-ALL.
CAR contains three basic elements—the extracellularantigen binding domain, transmembrane domain, and cytoplasmicsignaling domain. First-generation CAR featured asingle signaling domain most commonly derived from the CD3 component of TCR (T cell receptor)/ CD3 complex. Second or third-generation CAR was designed by including additional signaling domains, such as CD28 and/ or 4-1BB, that potentiate T-cell effector functions and activate co-stimulatory pathways, resulting in upregulation of genes encoding anti-apoptotic proteins and increased cytokine secretion. With this strategy, a complete remission for B-ALL patients who received CD19-targeting CAR-T cell therapy was achieved with up to >90% success rates [1].
The success in B-ALL treatment mainly contributed to using the B-ALL marker of CD19. The human CD19 antigen is a 95 kd transmembrane glycoprotein belonging to the immunoglobulin (Ig) superfamily, and expressed on follicular dendritic cells and B cells. In fact, it is present on B cells from earliest recognizable B-lineage cells during development to B-cell blasts, including B-ALL [2]. Thus, CD19 makes itself a perfect target for CAR-T cell therapy although B cell aplasia becomes a must occur side effect due to normal B cell elimination as well. However, the situation in T-ALL is quite complicated because T-ALL is a highly heterogeneous disease despite considerable efforts to identify immunophenotypic abnormalities have been made since 1990s [3].
Among those markers that have been characterized, CD7 is a very interesting molecule with therapeutic target potential for T-ALL. CD7 is a transmembrane glycoprotein which appears early in T cell ontogeny and is expressed by most T cells in the periphery. In our lab, we have observed that CD7 expression was missing in a subpopulation of ~10% mature human T cells and majority of those cells were CD4+, which is consistent with previous reports [3]. We also found that CD7 negative status lasts during the ex vivo expansion. Meanwhile, it has been demonstrated that the CD7 -/ CD8+ population seems to be a more persistent and stable population of effector cells [4]. One of the most important features for CD7 is that the expression level of CD7 increased ~75% in T-ALL cells comparing to the normal CD7+ T cells [5]. Therefore, CD7 is thought a best marker for T-ALL.
However, if CAR-T technology is pursued in this disease setting, the following two major challenges must be overcome. 1) most T cells, including CD7+ normal T cells, may be eliminated and resulted in severe immunodeficiency. In contrast, in B-ALL, monthly i.v. administration of Ig can compensate the loss of normal B cells; 2) the malignant T cells are not suitable to prepare CAR-T cells. Accordingly, to develop a clinically feasible CAR-T platform for T-ALL, we will preferably select CD7 as the target for above mentioned reason. In addition, CD7 negative normal T cells will be used to generate anti-CD7-CAR-T cells if the normal CD7- T cell is available in the patient. In this ideal scenario, CAR-T cells will kill the CD7+ T-ALL cells, and some adoptive memory anti-CD7- CAR- T cells may persist and provide essential cellular immunity for the patient. Furthermore, as long as the patient has some normal CD7- T cells, manufacturing of anti- CD7- CAR-T cells may not be an insurmountable obstacle because during the ex vivo expansion of CAR-T cells, the CD7+ T-ALL cells may be killed and CD7- normal cells with anti- CD7 CAR integrated will be selectively expanded. However, the patient may have insufficient normal CD7- T cells before or after ex vivo expansion. In this case, NK92 cell line may be the first choice to make an anti-CD7- CAR-NK cells to kill CD7+ T-ALL cells. Natural killer (NK) cells are critical for antiviral and anti-cancer immunity [6]. The central role of NK cells in immunity makes them an attractive subject of research and therapeutics. But autologous or allogeneic peripheral NK cells are also CD7+ cells, and hard to be transduced by viral vehicle. Thus, the activated NK cell line NK- 92 which has been proven highly cytotoxic against a broad spectrum of malignant cells [7], and can be grown in batch culture and under GMP conditions, make it a good candidate for anti-CD7-CAR driven cell therapy strategy. Although about ~70% of NK92 cells are CD7 positive, after the anti-CD7-CAR is stabilized in NK92 cells, only CD7 negative anti-CD7-CAR-NK cells survive because all CD7+ NK92 cells will be killed during the culture. We have established stable anti-CD7-CAR-NK cells which exhibited potent anti-CD7+ tumor cell efficacy (Figure 1). Recently, Silva et al reported that they used the CRISPR/Cas9 system to disrupt the CD7 gene in T cells prior to retroviral transduction with CD7-CAR. The CD7 gene was successfully disrupted in 90% of T cells, minimizing fratricide of CD7-CAR-T cells, and leading to a robust T cell expansion, similar to that of control T cells transduced with an irrelevant CAR, which may support the feasibility of using CD7-CAR-T cells for the targeted therapy of acute myeloid and lymphoid leukemia [8].
Future clinical trials may experience new challenges, including cytokine storm, neurotoxicity, and other common adverse events occurred in B-ALL CAR-T therapy, or insufficient clinical efficacy regarding CAR-NK therapy due to poor persistence of NK92 cells. However, CAR-T and/ or CAR-NK cell therapy may provide a new hope for those refractory/ relapsed T-ALL patients.


This work was supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Collaborative Innovation Major Project (Grant No. XYXT2015304), and Shandong Province Major R&D Project (NO. 2015GSF118108).


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