Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing

Ross, Sandra L.; Sherman, Marika; McElroy, Patricia; Lofgren, Julie A.; Moody, Gordon; Baeuerle, Patrick A.; Coxon, Angela; Arvedson, Tara

doi:10.1371/journal.pone.0183390

Cited by 78 publications

(63 citation statements)

References 49 publications

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“…In addition, the potency of either bispecific T-cell engager (BiTE) constructs or CAR-T cells depends on guiding the T cell to antigenpositive tumor cells. Bystander effects for BiTEs have therefore been reported to be dependent on proximity of the cytotoxic T cell to the target-negative tumor cell (37). Indeed, when in vivo activity of BAY 2287411 was tested in tumor models with varying target heterogeneity, in vivo activity was observed at H-scores as low as 25 and 80.…”

Section: Discussionmentioning

confidence: 99%

Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers

Hagemann¹,

Ellingsen

Schuhmacher

et al. 2019

Clinical Cancer Research

150

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Purpose: Targeted thorium-227 conjugates (TTC) represent a new class of molecules for targeted alpha therapy (TAT). Covalent attachment of a 3,2-HOPO chelator to an antibody enables specific complexation and delivery of the alpha particle emitter thorium-227 to tumor cells. Because of the high energy and short penetration range, TAT efficiently induces double-strand DNA breaks (DSB) preferentially in the tumor cell with limited damage to the surrounding tissue. We present herein the preclinical evaluation of a mesothelin (MSLN)-targeted thorium-227 conjugate, BAY 2287411. MSLN is a GPI-anchored membrane glycoprotein overexpressed in mesothelioma, ovarian, pancreatic, lung, and breast cancers with limited expression in healthy tissue. Experimental Design: The binding activity and radiostability of BAY 2287411 were confirmed bioanalytically. The mode-of-action and antitumor potency of BAY 2287411 were investigated in vitro and in vivo in cell line and patient-derived xenograft models of breast, colorectal, lung, ovarian, and pancreatic cancer. Results: BAY 2287411 induced DSBs, apoptotic markers, and oxidative stress, leading to reduced cellular viability. Furthermore, upregulation of immunogenic cell death markers was observed. BAY 2287411 was well-tolerated and demonstrated significant antitumor efficacy when administered via single or multiple dosing regimens in vivo. In addition, significant survival benefit was observed in a disseminated lung cancer model. Biodistribution studies showed specific uptake and retention of BAY 2287411 in tumors and enabled the development of a mechanistic pharmacokinetic/pharmacodynamic model to describe the preclinical data. Conclusions: These promising preclinical results supported the transition of BAY 2287411 into a clinical phase I program in mesothelioma and ovarian cancer patients (NCT03507452).

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Section: Discussionmentioning

confidence: 99%

Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers

Hagemann¹,

Ellingsen

Schuhmacher

et al. 2019

Clinical Cancer Research

150

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“…Because formation of the cytolytic synapse is independent of standard antigen recognition and costimulation mediated by major histocompatibility complex class I, lysis of the target tumor cell occurs in a manner that is independent of immune escape mechanisms that tumor cells may develop to evade detection. CD3ε is expressed by all CD8 + and CD4 + T cells, which enables polyclonal T-cell activation, expansion, cytokine production, and tumor cell lysis [51].…”

Section: Bispecific Antibody Constructsmentioning

confidence: 99%

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

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Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

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“…Another positive effect of arming OVs with T-cell engagers is the bystander effect demonstrated in specific cases. It has been shown that tumor cells negative for the target molecule of the engager (in this case EGFR) were lysed when in proximity to tumor cells that display the target antigen through T-cell induced bystander cell lysis ( 40 ). A phase II clinical trial has been reported for T-cell engager molecules which showed promising initial results but leaves room for improvement in terms of delivery regime in order to reduce the number of patients who need to drop out of the treatment early due to side effects.…”

Section: Strategies To Improve the Induction Of Tumor-specific Immunimentioning

confidence: 99%

Oncolytic Viral Therapy and the Immune System: A Double-Edged Sword Against Cancer

et al. 2018

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Oncolytic viral therapy is a new promising strategy against cancer. Oncolytic viruses (OVs) can replicate in cancer cells but not in normal cells, leading to lysis of the tumor mass. Beside this primary effect, OVs can also stimulate the immune system. Tumors are an immuno-suppressive environment in which the immune system is silenced in order to avoid the immune response against cancer cells. The delivery of OVs into the tumor wakes up the immune system so that it can facilitate a strong and durable response against the tumor itself. Both innate and adaptive immune responses contribute to this process, producing an immune response against tumor antigens and facilitating immunological memory. However, viruses are recognized by the immune system as pathogens and the consequent anti-viral response could represent a big hurdle for OVs. Finding a balance between anti-tumor and anti-viral immunity is, under this new light, a priority for researchers. In this review, we provide an overview of the various ways in which different components of the immune system can be allied with OVs. We have analyzed the different immune responses in order to highlight the new and promising perspectives leading to increased anti-tumor response and decreased immune reaction to the OVs.

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Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing

Cited by 78 publications

References 49 publications

Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers

Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

Oncolytic Viral Therapy and the Immune System: A Double-Edged Sword Against Cancer

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