Research And Grants

Preclinical assessment of efficacy and specificity of logic-gated CAR-T cell therapy in Diffuse Intrinsic Pontine Glioma

Proposal Abstract: Chimeric Antigen Receptor (CAR)-T cells have been clinically effective in patients with leukemias and lymphomas. Our goal is to bring similar success in treating a fatal brain tumor in children called DIPG (Diffuse Intrinsic Pontine Glioma). A major obstacle in treating brain tumors with CAR-T cell therapy is a lack of antigens that are tumor-specific or which are absent on normal vital tissues, which can lead to off-target toxicities. To overcome this risk, we have successfully generated “logic-gated” CAR-T cells targeting two distinct antigens, CD99 AND B7-H3, that are highly expressed on DIPG but present singly on certain normal cells. These gated “AND” CAR-Ts will have full activation against DIPG cells having both the antigens while sparing the single antigen-expressing normal cells. We propose to investigate 1) the specificity of these dual antigen-targeting CAR-T cells to kill only the DIPG tumor cells while protecting the normal cells; 2) the preclinical efficacy of these CAR-T cells using DIPG tumor-bearing mouse models and thereby assess the translational relevance to DIPG patients. The innovation of this proposal lies a) in the identification of a new antigen, CD99, as highly expressed in DIPG cells; b) in co-targeting CD99 with another previously reported tumor antigen, B7-H3, and c) in designing the CAR construct to pair each of these antigens with the signaling domain that will maximize the selectivity of our logic-gating for dual-antigen-positive tumor cells while mitigating the risk to single-antigen-positive cells from healthy tissues.

What questions will this study address? Our research addresses the critical and immediate need to develop a new therapy for DIPG. DIPG tumors are mainly restricted to the pons. and recent studies identified the involvement of other midline structures, including the thalamus. The tumor’s location makes it inoperable, and chemotherapy drugs are ineffective due to their inability to cross the blood-brain barrier and reach the tumor site. Therapy consists of radiation that provides only temporary relief.  This proposal will test a novel CAR-T base therapy as these T cells can go anywhere in the body and easily access the brain’s tumor site. This proposal will address the need to target more than one antigen to clear DIPG tumors and prevent toxicities to other normal tissues.

How will this study change the current standard of care? The current standard of care treatment for DIPG patients is only radiation therapy, which is palliative care, as the tumor relapses. Our dual antigen targeting gated CAR-T cell therapy is expected to open new therapeutic approaches in the field of immunotherapy for brain tumors in children.

What is the significance of this study? The single-antigen CAR-T cells have shown promise in early clinical trials for DIPG, but off-target toxicity can potentially limit their use. This proposal is significant because it aimed at eliminating DIPG tumor cells specifically without causing toxicity to normal cells and being potentially curative. This study results will also provide a proof-of-principle in using logic-gated CAR T cells in targeting other solid tumors with a heterogeneous expression of tumor antigen.

How will this study benefit DIPG patients and their families? This research has the potential to help DIPG patients and their families. DIPG is an aggressive brain tumor found in young kids and our research mainly applies to the pediatric population. This is the worst life-threatening brain tumor, with less than 2% survival compared to other pediatric and adult brain tumors. A life-threatening illness in a child can have a destructive effect on the whole family. Our study can improve the care of these patients by increasing their chance of survival.  

What are the future goals of this study? Successful completion of this work will provide an important step toward a new and effective therapeutic strategy for children with DIPG. This study will also provide data necessary to apply for an NIH-Ro1 grant to investigate the efficacy of combining this new CAR-T cell therapy with radiation to assess the effect of immunotherapy in patients’ tumors previously exposed to radiation and to establish the safety of the gated CAR-T cells using DIPG humanized mouse models. These studies will lead to IND enabling and FDA approval of the gated CAR-T cell therapy for DIPG patients.