Engineered T cells towards TNFRSF13C (<scp>BAFFR</scp>): a novel strategy to efficiently target B‐cell acute lymphoblastic leukaemia

Turazzi, Nice; Fazio, Grazia; Rossi, Valentina; Rolink, Antonius; Cazzaniga, Giovanni; Biondi, Andrea; Magnani, Chiara F.; Biagi, Ettore

doi:10.1111/bjh.14899

Cited by 16 publications

(14 citation statements)

References 10 publications

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“…While APRILdeficient mice have normal immune development, class switching to IgA and maintenance of serum IgA levels is highly APRIL-dependent. Specifically, anti-BAFF-R 16 and anti-BCMA 17 CARs are being developed for the treatment of B cell leukemia/lymphoma and multiple myeloma, respectively, while APRILexpressing CARs target TACI and BCMA expressing cells. 24 F I G U R E 1 BAFF, APRIL, and their receptors and splice variants: Both BAFF and APRIL multimerize: BAFF multimerizes into 60-mers via its flap region whereas APRIL multimerizes on cells surfaces by binding to proteoglycans.…”

Section: Aprilmentioning

confidence: 99%

“…13 Given relatively restricted expression on B cells, BAFF family receptors are potential targets for chimeric antigen receptor (CAR) T cell cancer therapies. Specifically, anti-BAFF-R 16 and anti-BCMA 17 CARs are being developed for the treatment of B cell leukemia/lymphoma and multiple myeloma, respectively, while APRILexpressing CARs target TACI and BCMA expressing cells. 18 Although currently restricted to oncology trials, these therapies could potentially be used to target B cell subsets in SLE…”

Section: Introductionmentioning

confidence: 99%

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BAFF inhibition in SLE—Is tolerance restored?

Jackson

Davidson

2019

Immunological Reviews

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The B cell activating factor (BAFF) inhibitor, belimumab, is the first biologic drug approved for the treatment of SLE, and exhibits modest, but durable, efficacy in decreasing disease flares and organ damage. BAFF and its homolog APRIL are TNF‐like cytokines that support the survival and differentiation of B cells at distinct developmental stages. BAFF is a crucial survival factor for transitional and mature B cells that acts as rheostat for the maturation of low‐affinity autoreactive cells. In addition, BAFF augments innate B cell responses via complex interactions with the B cell receptor (BCR) and Toll like receptor (TLR) pathways. In this manner, BAFF impacts autoreactive B cell activation via extrafollicular pathways and fine tunes affinity selection within germinal centers (GC). Finally, BAFF and APRIL support plasma cell survival, with differential impacts on IgM‐ and IgG‐producing populations. Therapeutically, BAFF and combined BAFF/APRIL inhibition delays disease onset in diverse murine lupus strains, although responsiveness to BAFF inhibition is model dependent, in keeping with heterogeneity in clinical responses to belimumab treatment in humans. In this review, we discuss the mechanisms whereby BAFF/APRIL signals promote autoreactive B cell activation, discuss whether altered selection accounts for therapeutic benefits of BAFF inhibition, and address whether new insights into BAFF/APRIL family complexity can be exploited to improve human lupus treatments.

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Section: Aprilmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BAFF inhibition in SLE—Is tolerance restored?

Jackson

Davidson

2019

Immunological Reviews

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“…The SB vector has recently been validated in clinical trials for the manufacture of CAR T cells (21) which were selectively propagated ex vivo with multiple stimulations in the presence of artificial antigen presenting cells (AaPCs). We have previously reported an improved platform of non-viral engineering using the SB vector which consist of a single stimulation step and was applied for different CAR molecules including anti-CD19, CD123 and BAFFR (22,23). Herein, we report the clinical application of this concept to treat adult and pediatric patients with B cell-ALL (B-ALL) relapsed post allogeneic hematopoietic stem cell transplantation (allo-HSCT) by using non-viral CD19-specific CARCIK cells (CARCIK-CD19) manufactured from the previous transplant donor.…”

Section: Introductionmentioning

confidence: 99%

Sleeping Beauty–engineered CAR T cells achieve antileukemic activity without severe toxicities

Magnani¹,

Gaipa²,

Lussana³

et al. 2020

Journal of Clinical Investigation

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134

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Background. Chimeric antigen receptor (CAR) T cell immunotherapy has achieved complete remission and durable response in highly refractory patients. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability. Methods. We reported the early results of a phase I/II trial in B-cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into cytokine induced killer cells (CIK). Results. The cellular product was produced successfully for all patients from the donor peripheral blood (PB) and consisted mostly of CD3+ lymphocytes with 43% CAR expression. Four pediatric and 9 adult patients were infused with a single dose of CAR T cells. Toxicities reported were two grade I and a grade II cytokine release syndrome (CRS) cases at the highest dose, in the absence of graftversus-host disease (GvHD), neurotoxicity, or dose-limiting toxicities. Six out of 7 patients, receiving the highest doses, achieved CR and CRi at day 28. Five out of 6 patients in CR were also minimal residual disease (MRD)-negative. Robust expansion was achieved in the majority of the patients. CAR T cells were measurable by transgene copy PCR up to 10 months. Integration site analysis showed a positive safety profile and highly polyclonal repertoire in vitro and at early time points after infusion. Conclusion. SB-engineered CAR T cells expand and persist in pediatric and adult BALL patients relapsed after HSCT. Anti-leukemic activity was achieved without severe toxicities. Trial registration. clinicaltrials.gov NCT03389035.

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“…They showed that short spacer CAR T cells genetically modified to express anti‐TSLPR chimeric antigen receptors can cure B‐ALL in xenograft models in CRLF2‐overexpressing ALL. In addition to TSLPR and CD22, other B‐cell markers such as ROR1 (inactive tyrosine‐protein kinase transmembrane receptor ROR1), Ig kappa (k) light chain, CD123 (the IL‐3 receptor a chain), and TNFRSF13C antigen were proposed as new targets for CAR T cells therapy.…”

Section: Future Directionsmentioning

confidence: 99%

The Evolution and Future of CAR T Cells for B‐Cell Acute Lymphoblastic Leukemia

Annesley

Summers

Ceppi

et al. 2017

Clin Pharma and Therapeutics

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Several CAR T designs with CD19 specificity have been associated with consistent responses in clinical trials with complete remission (CR) rates ranging from 70-90%. Relevant challenges remain to be addressed, such as production time, early loss of CAR T cells, relapse due to loss of the target antigen, and prevention of severe cytokine release syndrome and neurotoxicity. This review describes constructs, clinical trial results, side effects, and future direction of CAR T-cell therapy in B-ALL.

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Engineered T cells towards TNFRSF13C (BAFFR): a novel strategy to efficiently target B‐cell acute lymphoblastic leukaemia

Cited by 16 publications

References 10 publications

BAFF inhibition in SLE—Is tolerance restored?

BAFF inhibition in SLE—Is tolerance restored?

Sleeping Beauty–engineered CAR T cells achieve antileukemic activity without severe toxicities

The Evolution and Future of CAR T Cells for B‐Cell Acute Lymphoblastic Leukemia

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