Combination Therapy with Bispecific Antibodies and PD-1 Blockade Enhances the Antitumor Potency of T Cells

Chang, Chien-Hsing; Wang, Yang; Li, Rongxiu; Rossi, Diane L.; Liu, Donglin; Rossi, Edmund A.; Cardillo, Thomas M.; Goldenberg, David M.

doi:10.1158/0008-5472.can-16-3431

Cited by 68 publications

(38 citation statements)

References 52 publications

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“…Also noteworthy is a growing body of research focused on novel tumor-restricted immunotherapy strategies beyond the scope of this review. These promising approaches include: (i) Vaccines targeting neoantigens [259][260][261] ; (ii) Chimeric antigen receptor (CAR) T-cell therapy 262 ; (iii) Improved delivery of checkpoint blockade antibodies within the TME; (iv) Bispecific antibodies [263][264][265] ; and (v) Molecular shields restricting local activity of checkpoint inhibitors. 266 For future research, we propose studies designed to identify novel regulatory molecules that, when targeted, simultaneously enhance anti-tumor immunity yet suppress autoimmunity.…”

Section: Resultsmentioning

confidence: 99%

The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

Schnell¹,

Bod²,

Madi³

et al. 2020

Cell Res

157

104

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Co-inhibitory receptors are important regulators of T-cell function that define the balance between tolerance and autoimmunity. The immune regulatory function of co-inhibitory receptors, including CTLA-4, PD-1, TIM-3, TIGIT, and LAG-3, was first discovered in the setting of autoimmune disease models, in which their blockade or deficiency resulted in induction or exacerbation of the disease. Later on, co-inhibitory receptors on lymphocytes have also been found to influence outcomes in tumor and chronic viral infection settings. These receptors suppress T-cell function in the tumor microenvironment (TME), thereby making the T cells dysfunctional. Based on this observation, blockade of co-inhibitory receptors (also known as checkpoint molecules) has emerged as a successful treatment option for a number of human cancers. However, severe autoimmune-like side effects limit the use of therapeutics that block individual or combinations of co-inhibitory receptors for cancer treatment. In this review we provide an overview of the role of co-inhibitory receptors in autoimmunity and anti-tumor immunity. We then discuss current approaches and future directions to leverage our knowledge of co-inhibitory receptors to target them in tumor immunity without inducing autoimmunity.

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Section: Resultsmentioning

confidence: 99%

The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

Schnell¹,

Bod²,

Madi³

et al. 2020

Cell Res

157

104

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“…Most of the immune features observed in our study could be detected due to the presence of a fully intact immune system in our immune-competent mouse model, in which we applied mouse bsAb targeting the mouse CD3 protein and the mouse TAA to treat mouse melanoma in a syngeneic host. Most PDX interspecies models have used bispecifics targeting human CD3 and human tumor antigens, not expressed on mouse host tissues or immune cells (12,13,(16)(17)(18) and thus fail to monitor the full so-called on-target, off-tumor effects. Even the more elegant models in this research field, in which human CD3E is transgenically expressed in mouse T cells and human TAA are expressed in mouse tumor cell lines under heterologous promoters, fall short, due to artificial expression levels of the CD3 and TAA (21,22).…”

Section: Discussionmentioning

confidence: 99%

“…The activity and sensitivity of CD3 bsAbs are commonly evaluated in vitro using human cancer cell lines or 3D spheroid cultures (16). Further efficacy studies are subsequently performed in small laboratory animals, often xenograft mouse models, in which established human tumor cell lines or fresh tumor samples from patients are transplanted into immune-deficient mice (12,13,(16)(17)(18). Coengraftment of human peripheral blood mononuclear cells or purified T cells is required in these models to supply a source of immune effector cells.…”

Section: Introductionmentioning

confidence: 99%

CD3-Bispecific Antibody Therapy Turns Solid Tumors into Inflammatory Sites but Does Not Install Protective Memory

Benonisson

Altıntaş

Sluijter

et al. 2019

Molecular Cancer Therapeutics

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Immunotherapy of cancer with CD3-targeting bispecific antibodies (CD3 bsAb) is a fast developing field, and multiple tumor-associated antigens (TAA) are evaluated for hematologic and solid malignancies. The efficacy of these CD3 bsAb is usually examined in xenograft mouse tumor models with human T cells or in genetically engineered mouse models, where human TAA are introduced. These models often fail to fully recapitulate the natural tumor environment, especially for solid cancers, because of interspecies differences. Here, we investigated the systemic and intratumoral effects of a mouse CD3 bsAb in a fully immune-competent mouse melanoma model. Systemic administration of 0.5 mg/kg antibody induced a brief overall T-cell activation that was selectively sustained in the tumor microenvironment for several days. A fast subsequent influx of inflammatory macrophages into the tumor microenvironment was observed, followed by an increase in the number of CD4 þ and CD8 þ T cells. Although the capacity to directly kill melanoma cells in vitro was very modest, optimal tumor elimination was observed in vivo, even in the absence of CD8 þ T cells, implying a redundancy in T-cell subsets for therapeutic efficacy. Finally, we took advantage of the full immune competence of our mouse model and tested immune memory induction. Despite a strong initial immunity against melanoma, treatment with the CD3 bsAb did not install protective memory responses. The observed mechanisms of action revealed in this immune-competent mouse model might form a rational basis for combinatorial approaches.

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“…For those unresponsive patients, combining antibody drugs with different mechanisms might improve the effects of immunotherapy. 46 BS001 and PD-1/PD-L1 antibody combination therapy showed better outcome than monotherapy, which may represent a new option for patients.…”

Section: Discussionmentioning

confidence: 96%

<p>Suppression of c-Met-Overexpressing Tumors by a Novel c-Met/CD3 Bispecific Antibody</p>

Huang¹,

Xie²,

Li³

et al. 2020

DDDT

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Introduction Overexpression of c-Met, or hepatocyte growth factor (HGF) receptor, is commonly observed in tumor biopsies and often associated with poor patient survival, which makes HGF/c-Met pathway an attractive molecular target for cancer therapy. A number of antibody-based therapeutic strategies have been explored to block c-Met or HGF in cancers; however, clinical efficacy has been very limited, indicating that blockade of c-Met signal alone is not sufficient. Thus, an alternative approach is to develop an immunotherapy strategy for c-Met-overexpressing cancers. c-Met/CD3 bispecific antibody (BsAb) could bridge CD3-positive T lymphocytes and tumor cells to result in potent tumor cell killing. Materials and Methods A bispecific antibody, BS001, which binds both c-Met and CD3, was generated using a novel BsAb platform. Western blotting and T cells-mediated killing assays were utilized to evaluate the BsAb’s effects on cell proliferation, survival and signal transduction in tumor cells. Subcutaneous tumor mouse models were used to analyze the in vivo anti-tumor effects of the bispecific antibody and its combination therapy with PD-L1 antibody. Results BS001 showed potent T-cell mediated tumor cells killing in vitro. Furthermore, BS001 inhibited phosphorylation of c-Met and downstream signal transduction in tumor cells. In A549 lung cancer xenograft model, BS001 inhibited tumor growth and increased the proportion of activated CD56 + tumor infiltrating lymphocytes. In vivo combination therapy of BS001 with Atezolizumab (an anti-programmed cell death protein1-ligand (PD-L1) antibody) showed more potent tumor inhibition than monotherapies. Similarly, in SKOV3 xenograft model, BS001 showed a significant efficacy in tumor growth inhibition and tumor recurrence was not observed in more than half of mice treated with a combination of BS001 and Pembrolizumab. Conclusion c-Met/CD3 bispecific antibody BS001 exhibited potent anti-tumor activities in vitro and in vivo, which was achieved through two distinguished mechanisms: through antibody-mediated tumor cell killing by T cells and through inhibition of c-Met signal transduction.

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Combination Therapy with Bispecific Antibodies and PD-1 Blockade Enhances the Antitumor Potency of T Cells

Cited by 68 publications

References 52 publications

The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

CD3-Bispecific Antibody Therapy Turns Solid Tumors into Inflammatory Sites but Does Not Install Protective Memory

<p>Suppression of c-Met-Overexpressing Tumors by a Novel c-Met/CD3 Bispecific Antibody</p>

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