Potent CD4+ T cell-associated antitumor memory responses induced by trifunctional bispecific antibodies in combination with immune checkpoint inhibition

Deppisch, Nina; Rosenberger, Peter; Eißler, Nina; Lindhofer, Horst; Mocikat, Ralph

doi:10.18632/oncotarget.13888

Cited by 10 publications

(15 citation statements)

References 38 publications

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“…Concerning bAb-treatment, this is of interest as, similar to attenuation of MHC-dependent cytotoxic T cell responses, T cells redirected to EpCAM-positive target cells may become subdued by various mechanisms of immune inhibition such as PD-1/PD-L1 and CTLA-4/CD80/86 [36]. Indeed, treatment with EpCAM/CD3-bAb in a murine melanoma model resulted in upregulation of the immune checkpoint molecule CTLA-4 on recruited T cells in vivo and CTLA-4 blockade enhanced the humoral antimelanoma response with moderate survival benefit [37]. Combination of checkpoint inhibition and redirected T cell-mediated tumor cell lysis by bAbs is therefore deemed promising.…”

Section: Discussionmentioning

confidence: 99%

Targeting EpCAM by a Bispecific Trifunctional Antibody Exerts Profound Cytotoxic Efficacy in Germ Cell Tumor Cell Lines

Schönberger

Kraft²,

Nettersheim

et al. 2020

Cancers

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Outcome in high-risk patients with refractory or relapsed germ cell tumours (GCT) remains poor. Novel strategies enhancing therapeutic efficacy whilst limiting therapeutic burden are warranted, yet immunotherapy approaches geared towards activating endogenous antitumor responses have not been successful thus far. Redirection of cytotoxic effector cells by bispecific antibodies represents a promising approach in this setting. We demonstrate that the Epithelial Cell Adhesion Molecule (EpCAM) is broadly expressed in GCT cell lines of different histologic origin including seminoma, choriocarcinoma (CHC), and embryonal carcinoma (EC). In these GCT lines of variable EpCAM surface expression, targeting T cells by the prototypic bispecific EpCAM/CD3-antibody (bAb) Catumaxomab together with natural killer (NK) cell engagement via the Fc domain promotes profound cytotoxicity across a broad range of antibody dilutions. In contrast, tumor cell lysis mediated by either immune cell subset alone is influenced by surface density of the target antigen. In the CHC line JAR, NK cell-dependent cytotoxicity dominates, which may be attributed to differential surface expression of immunomodulatory proteins such as MHC-I, CD24, and Fas receptors on CHC and EC. In view of redirecting T cell therapy mediated by bispecific antibodies, such differences in GCT immunophenotype potentially favoring immune escape are worth further investigation.

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Section: Discussionmentioning

confidence: 99%

Targeting EpCAM by a Bispecific Trifunctional Antibody Exerts Profound Cytotoxic Efficacy in Germ Cell Tumor Cell Lines

Schönberger

Kraft²,

Nettersheim

et al. 2020

Cancers

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“…A notion that might counteract this limitation is epitope spreading occurring under active immunotherapy. Evidence for epitope spreading comes from preclinical studies with catumaxomab and a BiTE targeting an intracellular oncoprotein ( 33 , 34 ). However, the setting where blinatumomab is applied might not be beneficial for epitope spreading as these patients frequently have pancytopenia either as consequence of disease or treatment and might not be able to mount an effective T cell response.…”

Section: Limitations and Resistance Mechanisms To Tabsmentioning

confidence: 99%

“…While so far a major focus of research has been on the PD1-PD-L1 axis based on the mode of action which is predicted to be at the tumor site, the use of the other approved checkpoint axis blocker against CTLA4 (ipilimumab) has also been investigated. CTLA4 blockade ameliorates the activity of TABs, although to a more modest extent than seen with PD1 or PD-L1 blockade ( 33 ). Some studies, also indicate that blockade of both axes is required to achieve superior tumor cell killing ( 46 ).…”

Section: Combination Of Tabs With Checkpoint Blockadementioning

confidence: 99%

Rationale for Combining Bispecific T Cell Activating Antibodies With Checkpoint Blockade for Cancer Therapy

et al. 2018

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T cells have been established as core effectors for cancer therapy; this has moved the focus of therapeutic endeavors to effectively enhance or restore T cell tumoricidal activity rather than directly target cancer cells. Both antibodies targeting the checkpoint inhibitory molecules programmed death receptor 1 (PD1), PD-ligand 1 (PD-L1) and cytotoxic lymphocyte activated antigen 4 (CTLA4), as well as bispecific antibodies targeting CD3 and CD19 are now part of the standard of care. In particular, antibodies to checkpoint molecules have gained broad approval in a number of solid tumor indications, such as melanoma or non-small cell lung cancer based on their unparalleled efficacy. In contrast, the efficacy of bispecific antibody-derivatives is much more limited and evidence is emerging that their activity is regulated through diverse checkpoint molecules. In either case, both types of compounds have their limitations and most patients will not benefit from them in the long run. A major aspect under investigation is the lack of baseline antigen-specific T cells in certain patient groups, which is thought to render responses to checkpoint inhibition less likely. On the other hand, bispecific antibodies are also restricted by induced T cell anergy. Based on these considerations, combination of bispecific antibody mediated on-target T cell activation and reversal of anergy bears high promise. Here, we will review current evidence for such combinatorial approaches, as well as ongoing clinical investigations in this area. We will also discuss potential evidence-driven future avenues for testing.

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“…In the case of immune checkpoint blockade therapy, it was recently shown that an increase in a subset of central “memory-like” (CD27 + Fas − CD45RA − CCR7 + ) CD4 + T cells in patients with malignant melanoma could be used as a predictor of clinical response to PD-1 blockade therapy (190, 191). In fact, CD4 + T cell memory could be induced by tri-specific antibody treatment targeting immune checkpoint inhibitors to the tumor and activating tumor-specific both CD4 + and CD8 + T cells simultaneously, with the greatest effect observed in the CD4 + T EM and T CM compartments in mice (192). Thus, there is great therapeutic potential in harnessing the power of memory CD4 + T cells to promote the most effective anti-tumor immune responses.…”

Section: T Cell Responses To Cancer and Cancer-associated Antigensmentioning

confidence: 99%

Striking a Balance—Cellular and Molecular Drivers of Memory T Cell Development and Responses to Chronic Stimulation

et al. 2019

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Effective adaptive immune responses are characterized by stages of development and maturation of T and B cell populations that respond to disturbances in the host homeostasis in cases of both infections and cancer. For the T cell compartment, this begins with recognition of specific peptides by naïve, antigen-inexperienced T cells that results in their activation, proliferation, and differentiation, which generates an effector population that clears the antigen. Loss of stimulation eventually returns the host to a homeostatic state, with a heterogeneous memory T cell population that persists in the absence of antigen and is primed for rapid responses to a repeat antigen exposure. However, in chronic infections and cancers, continued antigen persistence impedes a successful adaptive immune response and the formation of a stereotypical memory population of T cells is compromised. With repeated antigen stimulation, responding T cells proceed down an altered path of differentiation that allows for antigen persistence, but much less is known regarding the heterogeneity of these cells and the extent to which they can become “memory-like,” with a capacity for self-renewal and recall responses that are characteristic of bona fide memory cells. This review focuses on the differentiation of CD4 + and CD8 + T cells in the context of chronic antigen stimulation, highlighting the central observations in both human and mouse studies regarding the differentiation of memory or “memory-like” T cells. The importance of both the cellular and molecular drivers of memory T cell development are emphasized to better understand the consequences of persisting antigen on T cell fates. Integrating what is known and is common across model systems and patients can instruct future studies aimed at further understanding T cell differentiation and development, with the goal of developing novel methods to direct T cells toward the generation of effective memory populations.

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Potent CD4+ T cell-associated antitumor memory responses induced by trifunctional bispecific antibodies in combination with immune checkpoint inhibition

Abstract: ABSTRACT

Cited by 10 publications

References 38 publications

Targeting EpCAM by a Bispecific Trifunctional Antibody Exerts Profound Cytotoxic Efficacy in Germ Cell Tumor Cell Lines

Targeting EpCAM by a Bispecific Trifunctional Antibody Exerts Profound Cytotoxic Efficacy in Germ Cell Tumor Cell Lines

Rationale for Combining Bispecific T Cell Activating Antibodies With Checkpoint Blockade for Cancer Therapy

Striking a Balance—Cellular and Molecular Drivers of Memory T Cell Development and Responses to Chronic Stimulation

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