Anti-CCR9 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia

Maciocia, Paul; Wawrzyniecka, Patrycja; Maciocia, Nicola; Burley, Amy; Karpanasamy, Thaneswari; Devereaux, S; Hoekx, Malika; O’Connor, David; León, Theresa E.; Rapoz-D'Silva, Tanya; Pocock, Rachael; Rahman, Sunniyat; Gritti, Giuseppe; Yánez, Diana C.; Ross, Susan R.; Crompton, Tessa; Williams, Owen; Lee, Lydia Sarah Hui; Pulé, Martin; Mansour, Marc R.

doi:10.1182/blood.2021013648

Cited by 44 publications

(36 citation statements)

References 59 publications

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“…Taken together, these data indicate the relevance of CCR9 expression levels in hematopoietic and non-hematopoietic tumors, as well as its effects on survival, suggesting that CCR9 might represent a relevant therapeutic target. The expression of CCR9 at the mRNA and protein levels in T-ALL has been recently confirmed by others ( 37 ).…”

Section: Resultssupporting

confidence: 55%

Therapeutic potential of an anti-CCR9 mAb evidenced in xenografts of human CCR9+ tumors

et al. 2022

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Relapsed or refractory T acute lymphoblastic leukemia (T-ALL) still carries poor prognosis. Aiming to improve outcomes, the therapeutic potential of an anti-CCR9 monoclonal antibody (mAb 92R), targeting the human chemokine-receptor CCR9 is analyzed on orthotopic xenotransplants. 92R mAb treatment of mice carrying human CCR9+ T-ALL cell lines or primary T cell leukemias inhibits tumor growth and increases survival. The therapeutic effects of 92R are specific and synergize with chemotherapeutic agents increasing survival. Furthermore, 92R decreases size of non-hematopoietic tumors with a forced CCR9 expression and of solid tumors generated by the pancreatic adenocarcinoma cell line AsPC-1. In addition, a humanized version of 92R mAb (Srb1) is also able to inhibit growth of CCR9+ T-ALL tumor cells in vivo, increasing survival 2.66-fold. Finally, 92R mAb prevents liver accumulation of infiltrates and reduces tumor cell numbers in already formed infiltrates. Thus, the humanized version of 92R mAb (Srb1), displays therapeutic potential for CCR9+ tumor treatment and might represent one of the first therapeutic antibodies for precision medicine on T-ALL patients.

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Section: Resultssupporting

confidence: 55%

Therapeutic potential of an anti-CCR9 mAb evidenced in xenografts of human CCR9+ tumors

et al. 2022

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“…(15) In this and the UKALL14 adult dataset(16) CR2 correlated with the NOTCH1 target Deltex 1, with only limited correlation with CCR9, consistent with NOTCH control of CD21 expression. (11) (Supplementary Fig. 1A-D) Further, we compared CD21 expression to previously described T-ALL selective targets CCR9 and CD1a (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Targeting antigens only expressed on T-ALL blasts, without expression on normal T cells (e.g. TRBC1, CD1a, CCR9) (9)(10)(11), is a more desirable strategy. However, this latter approach is limited since only a proportion of T-ALL cases express target-selective antigens.…”

Section: Introductionmentioning

confidence: 99%

Anti-CD21 Chimeric Antigen Receptor T cells for the Treatment of T Cell Acute Lymphoblastic Leukemia

Maciocia

Burley

Hoekx

et al. 2022

Preprint

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Relapsed/refractory (R/r) T cell acute lymphoblastic leukemia (T-ALL) has a dismal prognosis, with an unmet need for effective novel therapies. The successes seen in chimeric antigen receptor (CAR)-T cell therapy for B-ALL have yet to be fully translated to T-ALL. Most strategies have targeted pan-T antigens (CD7, CD5) but these may be limited by T cell aplasia and fratricide, requiring elimination of CAR-T antigen expression during manufacture and salvage hematopoietic stem cell transplantation (HSCT). Here, we describe CD21 as a novel immunotherapeutic strategy for the treatment of T-ALL. CD21 is largely confined to malignant T cells with expression in 57% of diagnostic T-ALL but only on a minor fraction of mature T cells (10%). While anti-CD21 CAR-T targeting membrane distal epitopes were ineffective, CAR-T cells utilising a novel Fab-CAR architecture and binding to membrane proximal epitopes showed no fratricide and were potent against low antigen density cell line and patient-derived xenograft models of T-ALL in vitro and in vivo. Further, we showed that CD21 expression in T-ALL can be upregulated by inhibition of the PI3K/ axis. CD21 is a novel target for CAR-T cell therapy in T-ALL, avoiding the fratricide and T cell aplasia seen with many T-ALL CAR-T strategies.

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“…Thus, it represents an ideal target for CCR9 positive T-ALL. In preclinical studies, anti-CCR9 CAR-T cells exhibited potent anti-leukemic activity and were resistant to fratricide (37).…”

Section: Targets For Car-t Cell Therapy In T Cell Lymphoblastic Leuke...mentioning

confidence: 99%

CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges

et al. 2022

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Chimeric antigen receptor T (CAR-T) cell therapy represents a major breakthrough in cancer treatment, and it has achieved unprecedented success in hematological malignancies, especially in relapsed/refractory (R/R) B cell malignancies. At present, CD19 and BCMA are the most common targets in CAR-T cell therapy, and numerous novel therapeutic targets are being explored. However, the adverse events related to CAR-T cell therapy might be serious or even life-threatening, such as cytokine release syndrome (CRS), CAR-T-cell-related encephalopathy syndrome (CRES), infections, cytopenia, and CRS-related coagulopathy. In addition, due to antigen escape, the limited CAR-T cell persistence, and immunosuppressive tumor microenvironment, a considerable proportion of patients relapse after CAR-T cell therapy. Thus, in this review, we focus on the progress and challenges of CAR-T cell therapy in hematological malignancies, such as attractive therapeutic targets, CAR-T related toxicities, and resistance to CAR-T cell therapy, and provide some practical recommendations.

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Anti-CCR9 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia

Cited by 44 publications

References 59 publications

Therapeutic potential of an anti-CCR9 mAb evidenced in xenografts of human CCR9+ tumors

Therapeutic potential of an anti-CCR9 mAb evidenced in xenografts of human CCR9+ tumors

Anti-CD21 Chimeric Antigen Receptor T cells for the Treatment of T Cell Acute Lymphoblastic Leukemia

CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges

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