The Israeli Ministry of Health (MOH) a Phase I/II trial of Enlivex Therapeutics Ltd.’s (NASDAQ: 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.

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 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 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.

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 (NYSE: MRK) Keytruda or Bristol-Myers Squibb Co.’s (NYSE: BMY) YERVOY, struggle to bypass the cancer’s new defenders.

This challenge has resulted in response rates as low as 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 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 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 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.

As part of a new generation of companies representing the future of cell therapy – off-the-shelf, highly scalable and low COGS “beyond CAR-T” cell therapies – Enlivex is focused on a highly differentiated novel immunotherapeutic mechanism – macrophage homeostasis. Macrophage homeostasis is severely disrupted by certain diseases states, and such imbalance is critical to the progression of the diseases. Allocetra has the potential to introduce highly-effective, low-cost allogeneic cell therapies for life-threatening clinical indications that are defined as "unmet medical needs", including sepsis – one of the leading causes of mortality, and oncology, through restoration of macrophage homeostasis. Enlivex is led by a seasoned management team who founded PROLOR Biotech and led it to a successful $560 financial exit and a partnership with Pfizer. PROLOR’s lead product, now named NGenla® by Pfizer, recently received marketing approval in Australia, Canada, Japan and the EU.

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Safe Harbor Statement: This press release contains forward-looking statements, which may be identified by words such as “expects,” “plans,” “projects,” “will,” “may,” “anticipates,” “believes,” “should,” “would”, “could,” “intends,” “estimates,” “suggests,” “has the potential to” and other words of similar meaning, including statements regarding expected cash balances, market opportunities for the results of current clinical studies and preclinical experiments, the effectiveness of, and market opportunities for, ALLOCETRATM programs. All such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Investors are cautioned that forward-looking statements involve risks and uncertainties that may affect Enlivex’s business and prospects, including the risks that Enlivex may not succeed in generating any revenues or developing any commercial products; that the products in development may fail, may not achieve the expected results or effectiveness and/or may not generate data that would support the approval or marketing of these products for the indications being studied or for other indications; that ongoing studies may not continue to show substantial or any activity; and other risks and uncertainties that may cause results to differ materially from those set forth in the forward-looking statements. The results of clinical trials in humans may produce results that differ significantly from the results of clinical and other trials in animals. The results of early-stage trials may differ significantly from the results of more developed, later-stage trials. The development of any products using the ALLOCETRATM product line could also be affected by a number of other factors, including unexpected safety, efficacy or manufacturing issues, additional time requirements for data analyses and decision making, the impact of pharmaceutical industry regulation, the impact of competitive products and pricing and the impact of patents and other proprietary rights held by competitors and other third parties. In addition to the risk factors described above, investors should consider the economic, competitive, governmental, technological and other factors discussed in Enlivex’s filings with the Securities and Exchange Commission, including in the Company’s most recent Annual Report on Form 20-F filed with the Securities and Exchange Commission. The forward-looking statements contained in this press release speak only as of the date the statements were made, and we do not undertake any obligation to update forward-looking statements, except as required under applicable law.

Shachar Shlosberger