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The Israeli Ministryof Health (MOH) approved a Phase I/II trial of Enlivex Therapeutics Ltd. ’s (NASDAQ:ENLV) proprietary immunotherapy drug-candidate AllocetraTM.
AllocetraTM is a celltherapy that uses healthy donor cells to reprogram and strengthen thepatient’s immune response against cancer.
If approved, the drugcandidate would be a universal, off-the-shelf immunotherapy that couldbe combined with other leading immunotherapies and cancer treatmentsto improve a patient’s odds of beating this hard-to-treat disease.Here’s how the Israel-based biotech’s macrophage reprogrammingdrug works and what the latest clinical trial measures.
AllocetraTM Reprograms Macrophages To WeakenCancer Cells
Thefirst responders of the body’s immune systems, macrophages, patrolthe bloodstream looking for signs of infection. Once spotted, theyengulf the pathogen, rip it apart and alert other immune cells like Tcells that it’s time to take action.
When cancer cells grow in the body, thedisease evades detection by trickingmacrophages into believing the cancerous cell is a normal,healthy cell. Then, it can turn that macrophage into a pro-tumor allythat will suppress any immune response trying to kill the cancer.
With Allocetra,healthy donor cells are sent in to reprogram thepatient’s own macrophages so they not only stop helping thetumor but also start working with the immune system to fight thosecancer cells again.
To do that, Enlivex developed a proprietary process to programthose donor macrophages to send out an “eat me” signal onceinjected. That signal tells the patient’s macrophages to eat thedonor cells. Once engulfed, they set to work restoring it to itshomeostatic state.
RestoringMacrophage Homeostasis Could Help Overcome Checkpoint InhibitorResistance
Whilereprogramming macrophages may already help boost the body’scancer-fighting ability on its own, one of the most excitingpotentials of this novel treatment is its ability to combat theresistance that cancers often develop against other immunotherapies.
Because cancercan 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 SquibbCo. ’s (NYSE: BMY) YERVOY, struggle to bypass the cancer’s newdefenders.
Thischallenge has resulted in response rates as low as 13% tothese novel treatments. That figure is disappointing because, intheory, checkpoint inhibitors are extremely promising. Checkpointslike PD-1 and CTLA-4, the ones blocked by Keytruda and YERVOY,respectively, are “off switches” that help the immune systemrecognize and avoid attacking the body’s own cells.
Just as cancer can trickmacrophages into coming to its defense, it can usethose checkpoints to trick the immune system into believingthe cancer cell is a normal cell. By blocking those checkpoints, thecancer is no longer able to escape detection in this way.
However, even when thosecheckpoints are blocked and the immune system kicks into action tofight the cancer cells it can now recognize, dysregulated macrophagesform a kind of protective layer on top of a tumor that prevents theimmune system from effectively attacking it.
It’s that last layerof defense that researchers think may play a role in the low responserate of checkpoint inhibitors. Enlivex hopes that AllocetraTM’spotential to reprogram those macrophages will help remove thatprotective barrier so that when the checkpoint inhibitor gets rid ofthe cancer’s “off switch,” the patient’s immune system won’thave any obstacles in its way to attacking that tumor.
The Phase I/II Clinical Trial Will StudyAllocetraTM Alone and in Combination with a CheckpointInhibitor
Therecent MOH approval paves the way for Enlivex to enroll up to 48patients with advanced solid tumors in a multicenter, open-label trialthat will include two stages. In stage one, patients will receiveescalating doses of AllocetraTM by itself. The intravenous injectionswill be administered once a week for three weeks.
In stage two, patientswill receive three injections of AllocetraTM in combination with ananti-PD1 checkpoint inhibitor. In preclinical studies, thiscombination resulted in 50%survival probability for mice with ovarian cancer, compared to15% or less for anti-PD1 checkpoint inhibitors on their own.
While the primaryobjective of the study is to evaluate the safety and tolerability ofAllocetraTM alone and in combination, researchers will also bemeasuring efficacy, including overall response rate, survival andprogression-free survival.
Enlivex says the new trial is slated to begin inthe third quarter of this year.
As part of a new generation ofcompanies 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 immunotherapeuticmechanism – macrophage homeostasis. Macrophage homeostasis isseverely disrupted by certain diseases states, and such imbalance iscritical to the progression of the diseases. Allocetra has thepotential to introduce highly-effective, low-cost allogeneic celltherapies for life-threatening clinical indications that are definedas "unmet medical needs", including sepsis – one of theleading causes of mortality, and oncology, through restoration ofmacrophage homeostasis. Enlivex is led by a seasoned management teamwho founded PROLOR Biotech and led it to a successful $560 financialexit and a partnership with Pfizer. PROLOR’s lead product, now namedNGenla® by Pfizer, recently received marketing approval in Australia,Canada, Japan and the EU.
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Safe HarborStatement: 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 otherwords of similar meaning, including statements regarding expected cashbalances, market opportunities for the results of current clinicalstudies and preclinical experiments, the effectiveness of, and marketopportunities for, ALLOCETRA TM programs. All suchforward-looking statements are made pursuant to the safe harborprovisions of the Private Securities Litigation Reform Act of 1995.Investors are cautioned that forward-looking statements involve risksand uncertainties that may affect Enlivex’s business and prospects,including the risks that Enlivex may not succeed in generating anyrevenues or developing any commercial products; that the products indevelopment may fail, may not achieve the expected results oreffectiveness and/or may not generate data that would support theapproval or marketing of these products for the indications beingstudied or for other indications; that ongoing studies may notcontinue to show substantial or any activity; and other risks anduncertainties that may cause results to differ materially from thoseset forth in the forward-looking statements. The results of clinicaltrials in humans may produce results that differ significantly fromthe results of clinical and other trials in animals. The results ofearly-stage trials may differ significantly from the results of moredeveloped, later-stage trials. The development of any products usingthe ALLOCETRA TM product line could also be affected by anumber of other factors, including unexpected safety, efficacy ormanufacturing issues, additional time requirements for data analysesand decision making, the impact of pharmaceutical industry regulation,the impact of competitive products and pricing and the impact ofpatents and other proprietary rights held by competitors and otherthird 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 withthe Securities and Exchange Commission, including in the Company’smost recent Annual Report on Form 20-F filed with the Securities andExchange Commission. The forward-looking statements contained in thispress release speak only as of the date the statements were made, andwe do not undertake any obligation to update forward-lookingstatements, except as required under applicablelaw.
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