Israeli Ministry Of Health Clears Way For Human Trials Of AllocetraTM, A Proprietary Off-the-Shelf Immunotherapy For Solid Tumors

The Israeli Ministry of Health (MOH) approved a Phase I/II trial of Enlivex Therapeutics Ltd.’s ENLV proprietary immunotherapy drug-candidate AllocetraTM. 

AllocetraTM is a cell therapy that uses healthy donor cells to reprogram and strengthen the patient’s immune response against cancer. 

If approved, the drug candidate would be a universal, off-the-shelf immunotherapy that could be combined with other leading immunotherapies and cancer treatments to improve a patient’s odds of beating this hard-to-treat disease. Here’s how the Israel-based biotech’s macrophage reprogramming drug works and what the latest clinical trial measures.

AllocetraTM Reprograms Macrophages To Weaken Cancer Cells

The first responders of the body’s immune systems, macrophages, patrol the bloodstream looking for signs of infection. Once spotted, they engulf the pathogen, rip it apart and alert other immune cells like T cells that it’s time to take action.

When cancer cells grow in the body, the disease evades detection by tricking macrophages into believing the cancerous cell is a normal, healthy cell. Then, it can turn that macrophage into a pro-tumor ally that will suppress any immune response trying to kill the cancer. 

With Allocetra, healthy donor cells are sent in to reprogram the patient’s own macrophages so they not only stop helping the tumor but also start working with the immune system to fight those cancer cells again.

To do that, Enlivex developed a proprietary process to program those donor macrophages to send out an “eat me” signal once injected. That signal tells the patient’s macrophages to eat the donor cells. Once engulfed, they set to work restoring it to its homeostatic state.

Restoring Macrophage Homeostasis Could Help Overcome Checkpoint Inhibitor Resistance

While reprogramming macrophages may already help boost the body’s cancer-fighting ability on its own, one of the most exciting potentials of this novel treatment is its ability to combat the resistance that cancers often develop against other immunotherapies. 

Because cancer can trick macrophages into defending tumors instead of attacking them, other immunotherapies, including checkpoint inhibitors like Merck & Co. Inc.’s MRK Keytruda or Bristol-Myers Squibb Co.’s BMY YERVOY, struggle to bypass the cancer’s new defenders. 

This challenge has resulted in response rates as low as 13% to these novel treatments. That figure is disappointing because, in theory, checkpoint inhibitors are extremely promising. Checkpoints like PD-1 and CTLA-4, the ones blocked by Keytruda and YERVOY, respectively, are “off switches” that help the immune system recognize and avoid attacking the body’s own cells.  

Just as cancer can trick macrophages into coming to its defense, it can use those checkpoints to trick the immune system into believing the cancer cell is a normal cell. By blocking those checkpoints, the cancer is no longer able to escape detection in this way. 

However, even when those checkpoints are blocked and the immune system kicks into action to fight the cancer cells it can now recognize, dysregulated macrophages form a kind of protective layer on top of a tumor that prevents the immune system from effectively attacking it.

It’s that last layer of defense that researchers think may play a role in the low response rate of checkpoint inhibitors. Enlivex hopes that AllocetraTM’s potential to reprogram those macrophages will help remove that protective barrier so that when the checkpoint inhibitor gets rid of the cancer’s “off switch,” the patient’s immune system won’t have any obstacles in its way to attacking that tumor. 

The Phase I/II Clinical Trial Will Study AllocetraTM Alone and in Combination with a Checkpoint Inhibitor

The recent MOH approval paves the way for Enlivex to enroll up to 48 patients with advanced solid tumors in a multicenter, open-label trial that will include two stages. In stage one, patients will receive escalating doses of AllocetraTM by itself. The intravenous injections will be administered once a week for three weeks. 

In stage two, patients will receive three injections of AllocetraTM in combination with an anti-PD1 checkpoint inhibitor. In preclinical studies, this combination resulted in 50% survival probability for mice with ovarian cancer, compared to 15% or less for anti-PD1 checkpoint inhibitors on their own. 

While the primary objective of the study is to evaluate the safety and tolerability of AllocetraTM alone and in combination, researchers will also be measuring efficacy, including overall response rate, survival and progression-free survival. 

Enlivex says the new trial is slated to begin in the third quarter of this year.

Featured photo by Ivan Samkov on Pexels

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