The progress in the field of Immuno-oncology just over the last few years has dramatically changed the clinical approach to treating malignancies, particularly those that become refractory to previously available interventions. Tremendous excitement centers on Adoptive Cell Therapy (ACT), an approach that delivers living cells derived from the human immunity system and engineered to target and kill cancer. Human T-cells are genetically modified to express Chimeric Antigen Receptors, or CARs, which selectively bind tumor antigens leading to potent tumor cell killing and CAR-T cell activation in a manner similar to an endogenous T-cell receptor. This approach aims to directly harness the power of T-cells to overcome problems of immune dysfunction and suppression that present formidable barriers to even checkpoint blockade therapy. Results from numerous ongoing clinical studies of CAR-T therapy are showing tremendous success and providing evidence of durable cancer remissions. While the first wave of approvals is anticipated this year, Xyphos is committed to the mission of developing a best-in-class CAR-T therapy platform based on convertibleCAR™ technology. Our vision is to bring precision and control to this revolutionary class of cancer treatments.
As with all new technologies, especially innovative medical interventions, there are frequent problems concurrent with the remarkable successes. A few significant problems that stem from standard CAR-T technology include:
- Lack of dose control of CAR-T cell activity, causing cytokine storm
- Uncontrollable on-target off-tumor toxicity
- Single antigen targeting permits tumor escape through antigen loss
- Many CARs in the clinic contain binding domains of non-human origin
convertibleCAR™-T cells can provide a solution to these frequent problems. convertibleCAR technology is based on a unique receptor-antibody control system engineered from protein components of the human NKG2D receptor/MIC ligand immune surveillance pathway. Through minimal mutation of the natural NKG2D receptor and directed evolution of small modular MIC domains that selectively bind the mutated NKG2D, we created an inert NKG2D CAR (iNKG2D CAR) that can only be activated using bispecific MIC-Antibody fusions (MicAbodies). The resulting platform enables a single iNKG2D CAR-T cell therapy to be precisely controlled using a tumor-specific MicAbody, and redirected to any antigen of choice.
This approach uniquely solves frequent CAR-T problems by affording the advantages of:
- Dose control of iNKG2D CAR-T cell activity to minimize cytokine storm
- Limiting on-target off-tumor toxicity by controlling MicAbody PK properties
- Ability to switch or multiplex targeting by simply using different MicAbodies
- Components are derived from human proteins to limit ADAs and improve persistence
We have demonstrated In vitro and in vivo proof-of-concept with impressive results with multiple convertibleCAR-T and MicAbody combinations showing precise targeting and dose-dependent control of the convertibleCAR-T system.