Dual targeting of CD19 and CD22 against B-ALL using a novel high-sensitivity aCD22 CAR

Kokalaki, Evangelia; Ma, Bin; Ferrari, Mathieu; Grothier, Thomas; Hazelton, Warren; Manzoor, Somayya; Costu, Eren; Taylor, Julia M.; Bulek, Anna; Srivastava, Saket; Gannon, Isaac; Jha, Ram; Gealy, Rosalind; Stanczuk, Lukas; Rizou, Tatiana; Robson, Mathew; Elkholy, M. M.; Baldan, Vania; Righi, Matteo; Sillibourne, James; Simon, Thomas; Onuoha, Shimobi; Cordoba, Shaun; Pulé, Martin

doi:10.1016/j.ymthe.2023.03.020

Cited by 19 publications

(12 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The adoptive transfer of T cells expressing a chimeric antigen receptor (CAR T) specific for B-cell lineage antigens such as CD19 and TNFRSF17 (BCMA) can induce rapid regression of relapsed or refractory lymphoma, acute leukemia and multiple myeloma [1][2][3][4][5][6]. Despite high initial response rates, a majority of patients relapse after CAR T treatment [2][3][4][5][6]. Heterogeneity in the expression level or complete loss of the target antigen on the tumor have been identified as frequent causes of relapse [8][9][10].…”

Section: Mainmentioning

confidence: 99%

“…We first evaluated monospecific full ChTCRs in which two different CD22 scFvs were fused to TRBC ( Fig 3a ). We tested the m971 scFv, which is used in the Loop CAR and targets a membrane proximal epitope, and the 9A8 scFv that targets a more membrane distal epitope ( Fig 3a ) [ 38 ]. ChTCRs were constructed in both V H V L and V L V H orientations, expressed in TRBC and TRAC edited T cells, and compared to conventional 4–1BBζ CARs constructed with the same scFvs ( Fig 3a ).…”

Section: Design Of a Sensitive Cd22 Monospecific Chtcrmentioning

confidence: 99%

“…CD8 + T cells were transduced with this Bi-ChTCR followed by TCR KO using CBE. For functional comparison, T cells were transduced with CD19 monospecific 4–1BBζ CAR, CD22 monospecific 4–1BBζ CAR using the m971 scFv, and with the bispecific Loop CAR [ 37 , 38 ] ( Fig 4a – b ). The MFI of rCD19 and rCD22 binding was superior for T cells expressing the Bi-ChTCR compared to the Loop CAR ( Fig 4b – d ).…”

Section: Design and Function Of Bispecific Cd19/cd22 Chtcrmentioning

confidence: 99%

“…

…”

mentioning

confidence: 99%

See 3 more Smart Citations

Sensitive bispecific chimeric T cell receptors for cancer therapy

Riddell,

Simon,

Bugos

et al. 2024

Preprint

View full text Add to dashboard Cite

The expression of a synthetic chimeric antigen receptor (CAR) to redirect antigen specificity of T cells is transforming the treatment of hematological malignancies and autoimmune diseases [1-7]. In cancer, durable efficacy is frequently limited by the escape of tumors that express low levels or lack the target antigen [8-12]. These clinical results emphasize the need for immune receptors that combine high sensitivity and multispecificity to improve outcomes. Current mono- and bispecific CARs do not faithfully recapitulate T cell receptor (TCR) function and require high antigen levels on tumor cells for recognition [13-17]. Here, we describe a novel synthetic chimeric TCR (ChTCR) that exhibits superior antigen sensitivity and is readily adapted for bispecific targeting. Bispecific ChTCRs mimic TCR structure, form classical immune synapses, and exhibit TCR-like proximal signaling. T cells expressing Bi-ChTCRs more effectively eliminated tumors with heterogeneous antigen expression in vivo compared to T cells expressing optimized bispecific CARs. The Bi-ChTCR architecture is resilient and can be designed to target multiple B cell lineage and multiple myeloma antigens. Our findings identify a broadly applicable approach for engineering T cells to target hematologic malignancies with heterogeneous antigen expression, thereby overcoming the most frequent mechanism of relapse after current CAR T therapies.

show abstract

Section: Mainmentioning

confidence: 99%

Section: Design Of a Sensitive Cd22 Monospecific Chtcrmentioning

confidence: 99%

Section: Design and Function Of Bispecific Cd19/cd22 Chtcrmentioning

confidence: 99%

“…

…”

mentioning

confidence: 99%

See 2 more Smart Citations

Sensitive bispecific chimeric T cell receptors for cancer therapy

Riddell,

Simon,

Bugos

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…The highly sensitive dual-targeting co-transduced CAR-T-cell therapy may be effective in preventing antigen escape. 15,16 Studies have reported CD19 CAR-T pharmacokinetics in patients with ALL and NHL, allowing scientists to acknowledge the associations between the characterization of the cellular kinetics of CD19 CAR-T and the efficacy or safety of these modalities. 17,18 Only two systematic reviews have documented the efficacy and safety of separated anti-CD20 or CD19 CAR-modified T cells for B-cell malignancies but not dualtargeting CD22/CD19-CAR-T-cell therapy.…”

Section: Introductionmentioning

confidence: 99%

Effectiveness and safety of CD22 and CD19 dual‐targeting chimeric antigen receptor T‐cell therapy in patients with relapsed or refractory B‐cell malignancies: A meta‐analysis

Nguyen,

Thanh Nhu,

Chen

et al. 2023

Cancer Medicine

View full text Add to dashboard Cite

BackgroundThe efficacy of CD22 or CD19 chimeric antigen receptor T (CAR‐T) cells in the management of acute lymphoblastic leukemia (ALL) and non‐Hodgkin lymphoma (NHL) was observed. Because antigen loss and lack of CAR‐T‐cell persistence are the leading causes of progressive disease following single‐antigen targeting, we evaluated CD22/CD19 dual‐targeting CAR‐T‐cell therapy efficacy and safety in relapsed/refractory B‐cell malignancies.MethodsThe Web of Science, PubMed, Cochrane, and Embase databases were searched until July 2022. Patients confirmed with any relapsed/refractory B‐cell hematological malignancies were included regardless of age, gender, or ethnicity, receiving CD22 and CD19‐dual‐targeting CAR‐T‐cell therapy. The studies conducted on patients with coexisting other cancer were excluded. We used random‐effect models to explore the outcome, and heterogeneity was investigated by subgroup analysis.ResultsFourteen studies (405 patients) were included. The pooled overall response (OR) and complete remission (CR) were 97% and 93%, respectively, for ALL patients. The 1‐year proportions of overall survival (OS) and progression‐free survival (PFS) were 70% and 49%, respectively. For NHL, OR occurred in 85% of patients, and 57% experienced CR. The results illustrated that the 1‐year OS and 1‐year PFS were 77% and 65%, respectively. The subgroup analysis showed that the dual‐targeting modality achieved higher CR in the following cases: coadministration of CD22/CD19‐CAR‐T cells and third‐generation CAR‐T cells combined with ASCT and BEAM pretreatment. The ALL and NHL groups seemed similar in treatment‐related toxicity: all grade cytokine release syndrome (CRS), severe CRS, and neurotoxicity occurred in 86%, 7%, and 12% of patients, respectively.ConclusionsOur meta‐analysis demonstrated that the CD22/CD19 dual‐targeting CAR‐T‐cell strategy has high efficiency with tolerable adverse effects in B‐cell malignancies.

show abstract

Mechanisms and strategies for safe chimeric antigen receptor T‐cell activity control

Stock,

Klüver,

Fertig

et al. 2023

Intl Journal of Cancer

View full text Add to dashboard Cite

The clinical application of chimeric antigen receptor (CAR) T‐cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood‐borne cancer types. However, CAR T‐cell therapy can lead to severe therapy‐associated toxicities including CAR‐related hematotoxicity, ON‐target OFF‐tumor toxicity, cytokine release syndrome (CRS) or immune effector cell‐associated neurotoxicity syndrome (ICANS). Just as CAR T‐cell therapy has evolved regarding receptor design, gene transfer systems and production protocols, the management of side effects has also improved. However, because of measures taken to abrogate adverse events, CAR T‐cell viability and persistence might be impaired before complete remission can be achieved. This has fueled efforts for the development of extrinsic and intrinsic strategies for better control of CAR T‐cell activity. These approaches can mediate a reversible resting state or irreversible T‐cell elimination, depending on the route chosen. Control can be passive or active. By combination of CAR T‐cells with T‐cell inhibiting compounds, pharmacologic control, mostly independent of the CAR construct design used, can be achieved. Other strategies involve the genetic modification of T‐cells or further development of the CAR construct by integration of molecular ON/OFF switches such as suicide genes. Alternatively, CAR T‐cell activity can be regulated intracellularly through a self‐regulation function or extracellularly through titration of a CAR adaptor or of a priming small molecule. In this work, we review the current strategies and mechanisms to control activity of CAR T‐cells reversibly or irreversibly for preventing and for managing therapy‐associated toxicities.

show abstract

Dual targeting of CD19 and CD22 against B-ALL using a novel high-sensitivity aCD22 CAR

Cited by 19 publications

References 68 publications

Sensitive bispecific chimeric T cell receptors for cancer therapy

Sensitive bispecific chimeric T cell receptors for cancer therapy

Effectiveness and safety of CD22 and CD19 dual‐targeting chimeric antigen receptor T‐cell therapy in patients with relapsed or refractory B‐cell malignancies: A meta‐analysis

Mechanisms and strategies for safe chimeric antigen receptor T‐cell activity control

Contact Info

Product

Resources

About