CD1a is rarely expressed in pediatric or adult relapsed/refractory T-ALL: implications for immunotherapy

Leong, Sarah; Inglott, Sarah; Papaleonidopoulou, Foteini; Orfinada, Karen; Ancliff, Philip; Bartram, Jack; Carpenter, Ben; Fielding, Adele K.; Ghorashian, Sara; Grandage, Victoria; Gupta, Rajeev; Hough, Rachael; Khwaja, Asim; Pavasovic, Vesna; Rao, Anupama; Samarasinghe, Sujith; Vora, Ajay; Mansour, Marc R.; O’Connor, David

doi:10.1182/bloodadvances.2020002502

Cited by 15 publications

(8 citation statements)

References 26 publications

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“…Recent positive pre‐clinical results have been achieved targeting the CD1a antigen expressed in cortical T‐ALL 119 . However, CD1a + T‐ALL has a good prognosis, meaning relapsed/refractory CD1a + T‐ALL is rare 120 …”

Section: Immunotherapymentioning

confidence: 99%

“…119 However, CD1a + T-ALL has a good prognosis, meaning relapsed/refractory CD1a + T-ALL is rare. 120 One approach to avoid CAR T cell fratricide is to delete the targeted antigen in the CAR T cells during CAR T cell production. This has been successfully achieved in an anti-CD7 CAR T cell that has its own CD7 loci disrupted by CRISPR/Cas9 genome editing.…”

Section: Chimeric Antigen Receptor Cellsmentioning

confidence: 99%

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Current and emerging therapeutic approaches for T‐cell acute lymphoblastic leukaemia

et al. 2021

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Summary T‐cell ALL (T‐ALL) is an aggressive malignancy of T‐cell progenitors. Although survival outcomes in T‐ALL have greatly improved over the past 50 years, relapsed and refractory cases remain extremely challenging to treat and those who cannot tolerate intensive treatment continue to have poor outcomes. Furthermore, T‐ALL has proven a more challenging immunotherapeutic target than B‐ALL. In this review we explore our expanding knowledge of the basic biology of T‐ALL and how this is paving the way for repurposing established treatments and the development of novel therapeutic approaches.

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Section: Immunotherapymentioning

confidence: 99%

Section: Chimeric Antigen Receptor Cellsmentioning

confidence: 99%

Current and emerging therapeutic approaches for T‐cell acute lymphoblastic leukaemia

et al. 2021

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“…CD38 is presently under investigation as a potential target for T-ALL. It is steadily expressed by T-ALL cells at presentation and primary refractory and relapsed/refractory stages [ 33 ], but also widely expressed within cells of the hematopoietic compartment and non-hematopoietic compartments, including the smooth muscle and pancreatic islets [ 34 ]. Even if the anti-CD38 daratumumab has been approved in multiple myeloma patients [ 35 ] and preclinically assessed against T-ALL [ 36 ], a careful clinical monitoring is required for on-target off-tumor toxicities in these frail patients.…”

Section: Discussionmentioning

confidence: 99%

“…CD1a is a surface glycoprotein expressed on approximately 40% of T-ALL cases, where it defines a cortical-derived T-ALL subgroup. CD1a expression is associated with an excellent clinical outcome; however, about 33% of relapsed/refractory patients still express CD1a [ 33 ]. In this regard, CD1a x CD3ε could provide an effective option for a subset of patients with poor therapeutic resources and dismal clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

A Novel Bispecific T-Cell Engager (CD1a x CD3ε) BTCE Is Effective against Cortical-Derived T Cell Acute Lymphoblastic Leukemia (T-ALL) Cells

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Caracciolo

Grillone

et al. 2022

Cancers

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy burdened by poor prognosis. While huge progress of immunotherapy has recently improved the outcome of B-cell malignancies, the lack of tumor-restricted T-cell antigens still hampers its progress in T-ALL. Therefore, innovative immunotherapeutic agents are eagerly awaited. To this end, we generated a novel asymmetric (2 + 1) bispecific T-cell engager (BTCE) targeting CD1a and CD3ε (CD1a x CD3ε) starting from the development of a novel mAb named UMG2. UMG2 mAb reacts against CD1a, a glycoprotein highly expressed by cortical T-ALL cells. Importantly, no UMG2 binding was found on normal T-cells. CD1a x CD3ε induced high T-cell mediated cytotoxicity against CD1a+ T-ALL cells in vitro, as demonstrated by the concentration-dependent increase of T-cell proliferation, degranulation, induction of cell surface activation markers, and secretion of pro-inflammatory cytokines. Most importantly, in a PBMC-reconstituted NGS mouse model bearing human T-ALL, CD1a x CD3ε significantly inhibited the growth of human T-ALL xenografts, translating into a significant survival advantage of treated animals. In conclusion, CD1a x CD3ε is a novel BTCE highly active against CD1a-expressing cortical-derived T-ALL cells suitable for clinical development as an effective therapeutic option for this rare and aggressive disease.

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“…The anti-CD38 antibody daratumumab, currently approved for the treatment of patients with multiple myeloma, is also being explored for patients with acute lymphoblastic leukemia (ALL), whose blasts commonly express high levels of CD38. 1 Patients with relapsed or refractory (R/R) disease, as well as those with positive measurable residual disease (MRD) have consistently shown unfavorable outcomes and, especially for T-lineage ALL, therapeutic options beyond first-line treatment remain limited. Preclinical studies have demonstrated that daratumumab has significant activity in human xenograft models of ALL, both as a single agent and in combination with chemotherapy.…”

mentioning

confidence: 99%

Daratumumab with or without chemotherapy in relapsed and refractory acute lymphoblastic leukemia. A retrospective observational Campus ALL study

et al. 2022

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CD1a is rarely expressed in pediatric or adult relapsed/refractory T-ALL: implications for immunotherapy

Cited by 15 publications

References 26 publications

Current and emerging therapeutic approaches for T‐cell acute lymphoblastic leukaemia

Current and emerging therapeutic approaches for T‐cell acute lymphoblastic leukaemia

A Novel Bispecific T-Cell Engager (CD1a x CD3ε) BTCE Is Effective against Cortical-Derived T Cell Acute Lymphoblastic Leukemia (T-ALL) Cells

Daratumumab with or without chemotherapy in relapsed and refractory acute lymphoblastic leukemia. A retrospective observational Campus ALL study

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