High Ex Vivo Response Rates to CD38/CD28xCD3 Trispecific T Cell Engager in Patients Relapsed after Anti-CD38 and Anti-BCMA Targeted Immunotherapies

Keller, Alana L.; de, Olivia Perez; Reiman, Lauren T; Walker, Z.; Jayabalan, David; Niesvizky, Rubén; Forsberg, Peter; Kim, Peter; Bisht, Kamlesh; Wang, Hongfang; Velde, Helgi van de; Sherbenou, Daniel W.

doi:10.1182/blood-2022-169072

Cited by 3 publications

(3 citation statements)

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“…The presence of the anti-CD28 domain in the TsAb enhanced T cell activation and killing of different MM cell lines in vitro, with superior potency compared with the anti-CD38 mAb daratumumab. Of note, this construct (renamed as CD38 TriAb) has shown significantly higher anti-MM cytotoxicity in ex vivo studies with primary MM samples and autologous T cells of patients relapsed after anti-CD38 and anti-BCMA immunotherapies compared to daratumumab and isatuximab [ 96 ]. Importantly, maximum MM cell killing in vitro was observed at CD38 TriAb concentrations far below serum levels well tolerated in NHP, precluding the side effects associated with potent CD28 stimulation in vivo.…”

Section: T Cell Engagersmentioning

confidence: 99%

Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies

Tapia-Galisteo,

Álvarez-Vallina,

Sanz

2023

J Hematol Oncol

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Immune cell engagers are engineered antibodies with at least one arm binding a tumor-associated antigen and at least another one directed against an activating receptor in immune effector cells: CD3 for recruitment of T cells and CD16a for NK cells. The first T cell engager (the anti-CD19 blinatumomab) was approved by the FDA in 2014, but no other one hit the market until 2022. Now the field is gaining momentum, with three approvals in 2022 and 2023 (as of May): the anti-CD20 × anti-CD3 mosunetuzumab and epcoritamab and the anti-B cell maturation antigen (BCMA) × anti-CD3 teclistamab, and another three molecules in regulatory review. T cell engagers will likely revolutionize the treatment of hematological malignancies in the short term, as they are considerably more potent than conventional monoclonal antibodies recognizing the same tumor antigens. The field is thriving, with a plethora of different formats and targets, and around 100 bispecific T cell engagers more are already in clinical trials. Bispecific NK cell engagers are also in early-stage clinical studies and may offer similar efficacy with milder side effects. Trispecific antibodies (engaging either T cell or NK cell receptors) raise the game even further with a third binding moiety, which allows either the targeting of an additional tumor-associated antigen to increase specificity and avoid immune escape or the targeting of additional costimulatory receptors on the immune cell to improve its effector functions. Altogether, these engineered molecules may change the paradigm of treatment for relapsed or refractory hematological malignancies.

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Section: T Cell Engagersmentioning

confidence: 99%

Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies

Tapia-Galisteo,

Álvarez-Vallina,

Sanz

2023

J Hematol Oncol

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“…The recognition of CD38 by SAR442257 would redirect T‐cells against MM 190,191 . SAR442257 showed a high response rate in samples from MM patients who relapsed after anti‐CD38 and anti‐BCMA therapy 192 . A number of other T‐cell engagers are also being developed, including elranatamab and cevostamab 193,194 …”

Section: Mechanisms Of Resistance Against Cd38 Antibodies and Potenti...mentioning

confidence: 99%

Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma

Bisht,

Fukao,

Chiron

et al. 2023

Cancer Medicine

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BackgroundCD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved—daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites.AimAmong the various mechanisms by which CD38 antibodies can induce MM cell death is immunomodulation, including multiple pathways for CD38‐mediated T‐cell activation. Patients who respond to anti‐CD38 targeting treatment experience more marked changes in T‐cell expansion, activity, and clonality than nonresponders.ImplicationsResistance mechanisms that undermine the immunomodulatory effects of CD38‐targeting therapies can be tumor intrinsic, such as the downregulation of CD38 surface expression and expression of complement inhibitor proteins, and immune microenvironment‐related, such as changes to the natural killer (NK) cell numbers and function in the bone marrow niche. There are numerous strategies to overcome this resistance, which include identifying and targeting other therapeutic targets involved in, for example, adenosine production, the activation of NK cells or monocytes through immunomodulatory drugs and their combination with elotuzumab, or with bispecific T‐cell engagers.

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“…In a related study by Keller et al ., RRMM patients previously treated with anti-CD38 and anti-BCMA responded well to CD38/CD28 × CD3 TsAb in vitro ( Abstract 169072 ). 21…”

Section: Tri-specific Antibodymentioning

confidence: 99%

Bispecific antibody treatment of multiple myeloma: latest updates from the 2022 ASH annual meeting

Yin,

Liu,

Sun

et al. 2023

Therapeutic Advances in Chronic Disease

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Background: Effective novel therapies for multiple myeloma (MM) patients who are unresponsive to conventional treatments (triple-class refractory) are an urgent need. Bispecific antibodies (BsAbs) offer a promising new approach to stimulate T cells and induce tumor cell death by targeting molecules on the surface of malignant plasma cells and CD3 on the surface of T cells. Objectives: Addressing the issue of improving the prognosis of triple-class refractory MM patients has become a significant clinical challenge. Design: This is a brief report. Methods: This article summarizes the latest updates of BsAbs treatment of MM from the 2022 ASH annual meeting. Results: BsAbs that target B-cell maturation antigen and G protein-coupled receptor family C group 5 memberD have demonstrated remarkable clinical activity and favorable safety profiles. Many potential targets for myeloma cells are currently undergoing phase I/II clinical trials, and these off-the-shelf bispecific molecules are likely to become a critical part of the MM treatment landscape. Conclusion: This article provides an overview of the latest advances in BsAbs immunotherapy for refractory and relapsed MM and highlights significant findings from the 2022 ASH annual meeting.

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High Ex Vivo Response Rates to CD38/CD28xCD3 Trispecific T Cell Engager in Patients Relapsed after Anti-CD38 and Anti-BCMA Targeted Immunotherapies

Cited by 3 publications

References 0 publications

Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies

Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies

Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma

Bispecific antibody treatment of multiple myeloma: latest updates from the 2022 ASH annual meeting

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