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Targeting Medulloblastoma with Multispecific Multivalent T-cell Engagers

Award Number: R01CA305103
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/22/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Targeting Medulloblastoma with Multispecific Multivalent T-cell Engagers - Treatment of the predominately pediatric CNS cancer, medulloblastoma (MB), is limited to neurosurgical resection, followed by radiation and cytotoxic chemotherapy. Unfortunately, for young patients standard of care can result in significant cognitive and motor dysfunction, secondary malignancies and endocrine dysfunction. In particular, although the prognosis for SHH MB (Group 2) is relatively good, there are currently no treatments for T53 mutant SHH MB, which comprise 20% of all SHH MB in children. Consequently, there is a critical and unmet need for new targeted and less toxic brain penetrant therapies for the treatment of SHH MB. Previously, our group has shown that two dihydrofolate reductase molecules (DHFR2 ) fused to distinct targeting ligands can spontaneously self-assemble upon the addition of a chemical dimerizer (bis-methotrexate (BisMTX)) into highly stable, multivalent, chemically selfassembled T-cell Engagers (CSAN-TE). Recently, we have shown that T-cells treated with bispecific CSAN-TE targeting either B7H3 undergo T-cell activation and targeted killing of SHH MB cancer cells both in vitro and in vivo. In addition, we have demonstrated that CSAN-TE comprised of a protein monomer incorporating an aTCR nanobody and either an aB7H3 affibody or aEGFR fibronectin are potent initiators of T-cell based TP53 wt and TP53 mut SHH MB cytotoxicity. In this proposal we will use our monomers to prepare brain penetrant trispecific aB7H3-aEGFR-aTCR-Ang-2 CSAN-TE. Our goal is to be able to induce T-cell induced SHH MB tumor eradication by targeting more than one SHH MB antigen, while enhancing CSAN-TE crossing of the BBB. A unique feature of our approach is the ability to deactivate the CSAN-TE by treatment with the brain-penetrant FDA-approved antibiotic trimethoprim, allowing us to deactivate the CSAN-TE pharmacologically, should immune activation based toxicity develop. In addition to drawing deeper insights into the factors governing the in vitro and in vivo potency of the trispecific CSAN-TE and potentially predict translational efficacy, we have begun to prepare predictive and hopefully translationally useful models of the in vitro and in vivo CSAN-TE T-cell targeted tumor killing capacity and biodistribution. The goals of this proposal are to; 1) develop and optimize trispecific aB7H3, aEGFR and aTCR multivalent CSAN-TE that are BBB penetrate and capable of eradicating SHH MB, and 2) develop predictive simulations of the in vitro cytotoxicity and in vivo biodistribution and anti-tumor activity of the trispecific and multivalent CSAN-TE. Animal Use Justification: In order to validate the ability of our CSAN-TE to cross the BBB, accumulate at the MB tumor site and induce targeted T-cell tumor eradication experiments with mouse models of MB will be required. The data from these experiments is also needed to build predictive mathematical models of the CSAN-TE action to inform future clinical translation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $2,238,024 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Cancer Treatment Research	000	1	9/17/2026	NEW	$2,238,024
														Subtotal = $2,238,024

Grand Total All Awards = $2,238,024

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Targeting Medulloblastoma with Multispecific Multivalent T-cell Engagers

Award Number: R01CA305103

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/22/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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