Curing γδ T Cell-Mediated Diseases

Slingshot Therapeutics is an early- stage biotechnology company developing potentially curative chimeric antigen receptor T cell therapies (CART) targeting γδ T cells. γδ T cell cancers are an ideal target for CART given the (1) historic success of CART in other hematologic cancers, (2) restricted expression of the γδ T cell receptor (TCR) with low expected risk of antigen escape due to reliance on TCR signaling for survival, and (3) predicted safety profile of depleting both cancerous and non-cancerous γδ T cells, as γδ T cells normally comprise approximately 5% of total peripheral T cells and thus their elimination is not expected to lead to global immunosuppression. Currently no other CAR T cell companies are specifically targeting γδ T cells to our knowledge. The potential for a curative therapy for these otherwise deadly cancers, which could subsequently be applied to various autoimmune and inflammatory conditions, would be highly valuable.

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The Scope of the Issue

γδ T cell leukemias and lymphomas (γδTCLL) are a group of aggressive neoplasms caused by the clonal proliferation of γδ T cells. γδTCLL is estimated to affect over 9,000 patients per year worldwide. Treatment primarily consists of polychemotherapy and radiation, but due to the highly refractory nature of disease, patients with γδTCLL have a median survival of 15 months, underscoring the extreme unmet need for effective therapy. Additionally, γδ T cells have been implicated in a number of inflammatory and autoimmune diseases including psoriasis, ankylosing spondylitis, and inflammatory myopathies.

Founding Team

Aimee Payne, MD, PhD

Christoph Ellebrecht, MD

Daniel Lundgren

Patrick Lundgren

Clinical Hypothesis

The central clinical hypothesis is that human T cells can be genetically programmed to eliminate malignant γδ T cell leukemias and lymphomas. Recently, the use of chimeric antigen receptor (CAR) T cells has been a major breakthrough in the treatment of hematopoietic malignancies, resulting in FDA approval of two CAR T cell products for refractory B cell leukemias and lymphomas. CARs consist of an antibody extracellular domain, fused to T cell cytoplasmic signaling and co-stimulatory domains. CARs redirect T cells to specifically kill cancer cells if they express the antigen targeted by the CAR, and also direct expansion and differentiation of memory CAR T cells that can provide lasting protection from cancer recurrence. CAR T cell therapies have led to lasting remissions of previously refractory B cell leukemias and lymphomas, and hence such an approach would be highly feasible for γδTCLL, due to the predicted favorable risk-benefit profile. Once proven safe and effective in γδTCLL, CART application to γδ T cell-mediated autoimmune and inflammatory diseases would be planned.

Key Messages

Lead indication focused on curing γδ T cell cancers

γδ T cell cancers are an ideal target for CAR T cells given past successes in blood cancers, highly restricted expression, and predicted safety profile
Founding team with experience developing engineered T cell products

Demonstrated efficacy and preliminary safety of lead asset in vivo

Patent filed and licensing negotiations are ongoing with Penn
Next 12-month value inflection point will be final IND-enabling studies focused on manufacturing and safety

Vision to to cure γδ T cell-mediated diseases spanning a breadth of diseases across autoimmunity and oncology

FOUNDING TEAM'S PREVIOUS WORK

See Aimee Payne's work on CAR T cell Therapy for Autoimmune Blistering Disease

In this video, Penn Medicine Dermatologist Aimee S. Payne, MD, PhD, and her research team at the Perelman School of Medicine at the University of Pennsylvania discuss their innovative investigational approach to engineering chimeric antigen receptor (CAR) T cells to treat pemphigus.

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