CD19

Tisagenlecleucel (tisa-cel), the first FDA-approved CAR-T-cell therapy, is a CD19-specific CAR containing the 4-1BB costimu latory domain and was initially approved for relapsed/refractory B-ALL based on the phase II ELIANA trial, which evaluated tisa-cel among 75 pediatric and young adult patients with B-ALL and dem onstrated a complete remission rate of 81% and overall survival of 70% at 18 months based on longer-term follow-up data. Cytokine release syndrome (CRS) and neurotoxicity (both discussed in more detail below), were seen in a substantial percentage of patients (see Table 1). Because the CD19 target molecule is also expressed by normal B cells, the eradication of B-cell leukemia is also associated with B-cell aplasia, which is typically sustained during the period of robust CAR-T cell engraftment. Among responders to tisa-cel who ultimately relapsed, 74% were found to have loss of CD19 expression on leukemic cells despite ongoing B-cell aplasia.

Table1. Selected Clinical Trials Using Chimeric Antigen Receptors−Modified and T-Cell Receptor−Modified T Cells

The phase II JULIET study evaluated tisa-cel in 93 patients with relapsed/refractory large B-cell lymphoma, and demonstrated overall and complete response rates of 52% and 40%, respectively, leading to FDA-approval for this indication as well. Axicabtagene ciloleucel (axi-cel) is another CD19-directed CAR which contains the CD28 costimulatory domain and was approved for the treatment of relapsed/refractory large B-cell lymphoma based on the phase II ZUMA-1 trial, which demonstrated overall and complete response rates of 82% and 54%, respectively. Finally, lisocabtagene maraleucel (liso-cel), a CD19-directed CAR containing the 4-1BB costimula tory domain with a modified hinge and transmembrane domain, has also been approved for relapsed/refractory large cell lymphoma based on the TRANSCEND NHL 001 trial, which demonstrated complete and overall response rates of 73% and 53%, respectively.

The efficacy of CD19-directed CAR-T-cell therapy has also been demonstrated in mantle cell lymphoma (MCL). The phase II ZUMA-2 trial evaluated brexucabtagene autoleucel, a CD19-directed CAR containing the CD28 costimulatory domain, in 74 patients with relapsed/refractory MCL, demonstrating overall and complete response rates of 85% and 59%, respectively.

B-Cell Maturation Antigen

CAR-T-cell therapies for multiple myeloma have also achieved promising results. B-cell maturation antigen (BCMA) has emerged as an important target antigen in multiple myeloma, and several BCMA-directed CAR-T-cell therapies are under development, with phase II studies demonstrating overall response rates of greater than 70% with impressive associated progression free survival benefits among patients with relapsed/refractory disease (see Table 1). Idecabtagene vicleucel (ide-cel), a BCMA-targeted CAR containing the 4-1BB costimulatory domain, was the first CAR-T-cell therapy to receive FDA approval for multiple myeloma. The phase II KarMMa study evaluated ide-cel among 140 patients with relapsed/refractory myeloma and demonstrated overall and complete response rates of 73% and 33%, respectively with a median progression-free survival of 8.8 months (see Table 1).

CD30

CAR-T-cell therapies for other hematologic malignancies are earlier in development, although several promising therapies are under investigation. For Hodgkin lymphoma and CD30+ non-Hodgkin lymphoma, CD30-directed CAR-T cells have also shown significant potential with a phase II study demonstrating an overall response rate of 72% (see Table 1).

Acute Myeloid Leukemia Targets

The identification of suitable target antigens for AML has remained a challenge largely because most AML-associated surface antigens are also expressed on normal hematopoietic stem cells, creating the potential for unacceptable on-target, off-tumor toxicities. Nonetheless, several ongoing trials are evaluating CD33- and CD123-specific CAR-T cells and other targets are also being evaluated (Table 2). Although few results have been reported to date, in a preliminary report of a phase I trial of CD123-specific CAR-T cells including 6 patients with AML, there were no significant myeloablative toxicities observed, and clinically meaningful responses were seen in two patients, one of whom achieved a CR and proceeded to a second allogeneic HSCT. One potential strategy to overcome limitations surrounding on-target, off-tumor hematopoietic toxicity in the treatment of AML is to use gene-editing techniques to remove the target antigen from donor hematopoietic stem cells prior to allogeneic HSCT, coupled with infusion of donor-derived allogeneic CAR-T cells. This was recently demonstrated in pre-clinical models using CRISPR/Cas9 editing to knock out CD33 from normal HSCs, followed by the infusion of CD33-specific CAR-T cells; however, the clinical feasibility of this approach is not yet clear. It remains to be seen whether toxicities, or efficacy concerns in the setting of possible antigen-negative relapse, will limit the feasibility of targeting a single antigen in myeloid malignancies and there is thus significant pre-clinical interest in combinatorial approaches, allowing the targeting of multiple antigens.

Table2. Target Antigens Under Evaluation for Chimeric Antigen Receptors T-cell Therapy

T-Cell Antigens

 Targeting of T-cell malignancies such as T-cell ALL (T-ALL) and T-cell lymphomas (TCL) with CAR-T cells has also been hampered by several added challenges. Because T-cell linage-associated antigens are typically shared by both normal and malignant T cells, CAR–T cell fratricide can interfere with the manufacturing process. CD5 is one potential target antigen that may be associated with less fratricide due to rapid downregulation of CD5 surface-expression on CAR-T cells. An initial clinical trial of CD5-targeted CAR-T cells among patients with T-cell malignancies has demonstrated promising pre liminary results, with objective responses seen in 4 of 9 evaluable patients. CRISPR/Cas9 gene editing to remove T-cell associated antigens from CAR-T cells is another technique that is being evaluated to prevent fratricide, and this strategy is currently being evaluated in several ongoing trials of both autologous and allogeneic CAR-T cells targeting CD7, which is highly expressed on both T and NK cells. CD30 is another potential target for certain TCLs, including anaplastic large cell lymphoma (ALCL). CD30 is expressed on only a small subset of activated T and B cells, so the risk of both fratricide and on-target, off-tumor toxicity is low. CD30-targeted CAR-T cells are being evaluated in several ongoing clinical trials and responses have been reported in a small number of patients with ALCL.

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مواضيع ذات صلة

Types of Cellular Immunotherapy

Adoptive Immunotherapy of Cancer

Therapeutic Manipulation of T-Cell-Mediated Immunity

T-Cell Exhaustion: Impaired Response after Chronic Antigen Exposure

T-Cell Memory

Regulatory T Cells

T-Cell Function

The T-Cell Receptor Complex

Antigen Presentation: Creating the Ligand for the T-Cell Receptor

Therapeutic Passive Immunization and Monoclonal Antibody Therapy

Adverse Events Related to Intravenous Immunoglobulin Infusion

Therapeutic use of Immunoglobulin : Intravenous Immunoglobulin