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Published on: May 16, 2020
Multivalent, Bispecific αB7-H3-αCD3 Chemically Self-Assembled Nanorings Direct Potent T Cell Responses against
Ellie A Mews1, Pauline Beckmann2, Mahathi Patchava2
1Department of Medicinal Chemistry, University of Minnesota, Cancer and Cardiovascular Research Building, 2231 Sixth Street SE, Minneapolis, Minnesota 55455 United States.
Abstract:
Few therapeutic options have been made available for treating central nervous system tumors, especially upon recurrence. Recurrent medulloblastoma is uniformly lethal with no approved therapies. Recent preclinical studies have shown promising results for eradicating various solid tumors by targeting the overexpressed immune checkpoint molecule, B7-H3. However, due to several therapy-related toxicities and reports of tumor escape, the full potential of targeting this pan-cancer antigen has yet to be realized. Here, we designed and characterized bispecific chemically self-assembling nanorings (CSANs) that target the T cell receptor, CD3ε, and tumor associated antigen, B7-H3, derived from the humanized 8H9 single chain variable fragment. We show that the αB7-H3-αCD3 CSANs increase T cell infiltration and facilitate selective cytotoxicity of B7-H3+ medulloblastoma spheroids and that activity is independent of target cell MHC class I expression. Importantly, nonspecific T cell activation against the ONS 2303 medulloblastoma cell line can be reduced by tuning the valency of the αCD3 targeted monomer in the oligomerized CSAN. Intraperitoneal injections of αB7-H3-αCD3 bispecific CSANs were found to effectively cross the blood-tumor barrier into the brain and elicit significant antitumor T cell activity intracranially as well as systemically in an orthotopic medulloblastoma model. Moreover, following treatment with αB7-H3-αCD3 CSANs, intratumoral T cells were found to primarily have a central memory phenotype that displayed significant levels of characteristic activation markers. Collectively, these results demonstrate the ability of our multivalent, bispecific CSANs to direct potent antitumor T cell responses and indicate its potential utility as an alternative or complementary therapy for immune cell targeting of B7-H3+ brain tumors.
Insights
New nanorings target B7-H3 and CD3ε to activate T cells against recurrent medulloblastoma. This therapy crosses the blood-tumor barrier, showing potent intracranial and systemic antitumor activity with potential for brain tumors.
Area of Science:
- Immunology
- Oncology
- Nanotechnology
Background:
- Limited therapeutic options exist for recurrent central nervous system tumors, particularly medulloblastoma.
- Targeting the immune checkpoint molecule B7-H3 shows promise for solid tumors but faces challenges with toxicity and tumor escape.
- B7-H3 is overexpressed in various solid tumors, making it a potential pan-cancer target.
Purpose of the Study:
- To design and characterize bispecific chemically self-assembling nanorings (CSANs) targeting B7-H3 and the T cell receptor CD3ε.
- To evaluate the efficacy of these CSANs in targeting B7-H3-positive medulloblastoma.
- To assess the potential of CSANs to overcome challenges associated with B7-H3 targeting therapies.
Main Methods:
- Development of bispecific CSANs targeting B7-H3 and CD3ε using a humanized single chain variable fragment.
- Assessment of T cell infiltration and cytotoxicity against B7-H3+ medulloblastoma spheroids.
- Evaluation of T cell activation and phenotype following CSAN treatment in an orthotopic medulloblastoma model.
- Investigation of the ability of CSANs to cross the blood-tumor barrier.
Main Results:
- αB7-H3-αCD3 CSANs enhanced T cell infiltration and selectively killed B7-H3+ medulloblastoma spheroids, independent of MHC class I expression.
- Nonspecific T cell activation was reduced by tuning CSAN valency.
- CSANs effectively crossed the blood-tumor barrier, inducing significant intracranial and systemic antitumor T cell activity.
- Treated tumors showed a T cell population with a central memory phenotype and activation markers.
Conclusions:
- Multivalent, bispecific CSANs can elicit potent antitumor T cell responses against B7-H3+ brain tumors.
- This CSAN platform demonstrates potential as an alternative or complementary therapy for brain tumors.
- The ability to modulate T cell activation and cross the blood-tumor barrier highlights the therapeutic potential of CSANs.
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