AffyImmune Therapeutics, an emerging leader in CAR-T therapies, today announced FDA approval of the company’s investigational new drug (IND) application for AIC100, an affinity-tuned CAR-T cell that received Orphan designation for advanced thyroid cancer. The trial: Phase I study of AIC100 in relapsed and or refractory advanced thyroid cancer and anaplastic thyroid cancer, is sponsored by Weill Cornell Medicine. The company’s AIC100 CAR-T cells effectively kill cells with high levels of ICAM-1, which is strongly overexpressed in advanced thyroid cancer.

Lower affinity CAR-T cells exhibit more robust antitumor activity

The initiation of this clinical trial is a significant milestone for CAR-T therapy as it utilizes CAR-T cells having roughly 1000-fold lower affinity to their target than most CAR-T cells used to date. These lower affinity CAR-T cells produce more robust and long-lasting anti-tumor activity than do high affinity CAR-T cells in animal models. Importantly, toxicity to healthy cells expressing basal levels of the target ICAM-1, seen with high-affinity CAR-T cells, was averted using CAR-T cells tuned to a lower-affinity.

AffyImmune co-founder and inventor of the technology, Moonsoo Jin, PhD stated, “this strategy can target antigens overexpressed in tumors without harming normal cells. As there are very few antigens that are purely tumor-associated, this opens the door to effectively targeting many tumor antigens that are otherwise very challenging.” Regarding the low efficacy observed to date using CAR-T cells against solid tumors in other studies, he continued, “CAR-T cells with an affinity-tuned targeting system demonstrate more robust and long-lasting anti-tumor activity, suggesting that a lower affinity targeting system prevents exhaustion of T cells and may also provide better serial killing of tumor cells after CAR-T therapy.”

AffyImmune CAR-T cells are traceable in vivo

In addition to enhanced longevity and anti-tumor activity, AffyImmune CAR-T cells are engineered for in vivo tracking using PET/CT imaging. Inclusion of the Somatostatin Type II receptor [SSTR2] enables real-time imaging of CAR-T cells using the approved radiotracer ⁶⁸Ga-DOTATATE with PET/CT scanning. SSTR2 specifically binds to the radiolabeled somatostatin analogue ⁶⁸Ga-DOTATATE.

Assessing the toxicity and efficacy of affinity-tuned CAR-T cells

Prior studies by Dr. Jin on LFA-1, a natural receptor for ICAM-1, resulted in the production of a range of LFA-1 affinity variants with a million-fold difference in binding affinities to ICAM-1. These were subsequently engineered into CAR-T cells and tested against a series of normal and tumor cells. Because LFA-1 interacts with ICAM-1 in human and murine models, toxicity and anti-tumor activity could be assessed simultaneously in animal models. Furthermore, ICAM-1 expression is upregulated by cytokines released during CAR-T cell-mediated killing of target cells. This means that if only 60% of tumor cells have high ICAM-1 levels, cytokines released during the killing of those cells cause the remaining ICAM-1-low tumor cells to upregulate ICAM-1, thereby becoming better targets themselves.

“Our preclinical data has shown that affinity-tuned CAR-T cells dramatically improve both their activity against solid tumors and safety,” said Dr. Eric von Hofe, President of AffyImmune. “The green light by the FDA gives us the opportunity to demonstrate the efficacy of this approach in patients who have an otherwise incurable disease.”

“We are very proud to have incubated AffyImmune since its inception,” said Simone Song, Senior Partner of ORI Healthcare Fund. “The goal of AffyImmune is to use CAR-T therapy to tackle solid tumors. What AffyImmune has achieved today is based on extensive basic science research as well as the founders’ perseverance at the discovery and enabling stage. Together with the management team, we hope to advance AffyImmune’s program to the next stage and do our part in addressing these unmet medical needs.”