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On November 13,Enlivex (NASDAQ: ENLV) announced that the firstpatient has been dosed in its Phase I/II clinical trial ofAllocetra. The novel off-the-shelf cell therapy is designed to helpbreak through the immune-suppressing tumor microenvironment – a keyroadblock rendering potent immunotherapies less effective againstsolid cancers – to render those tough-to-treat cancers moreresponsive to these treatments.
After a growing body of preclinical datademonstrated Allocetra’s potential to prolong survival duration andincrease survival probability in mice, the Phase I/II studies are animportant next step in evaluating their efficacy in humans.
Immunotherapies Tap the Body’s OwnCancer-Fighting Capabilities – But Solid Cancers RemainResistant
As thefield of immunotherapy makes strides, solid tumors continue to eludethese novel treatments largely due to their complex and ever-adapting“tumor microenvironments.” These microenvironments leverage arange of immune-suppressing mechanisms that counteract the potenteffects immunotherapies have had on skin and blood cancers.
Chimeric AntigenReceptor (CAR)-T therapies, for example, have demonstrated a successrate as high as 90% for refractory B lymphocytic leukemia but as low as 17% forsolid cancers. Novartis AG ’s (NYSE: NVS) Kymriah, the firstCAR-T therapy to receive approval from the Food and DrugAdministration, has since shown a durable remission and long-termsurvival rate, with as many as 55% of treated patients still alivemore than five years later compared to the standard disease prognosisof 10%to 25% .
The reason for this difference is largely due to the range ofmechanisms tumors use to resistor evade the immune system including disguising themselves ashealthy cells, releasing immune suppressing signals, and blockingimmune cells from getting into the core of the tumor. The more thetumor grows, the stronger these immunosuppressive mechanisms get –making it harder for the immune system to detect it.
This makes tumors someof the least responsive cells to immunotherapies of all kinds as thatmicroenvironment counteracts the effects of the treatment. Even incases where tumors do initially respond to the drug, they adaptto resist it and the once-helpful immunotherapy is renderedineffective.
AllocetraTM Uses CellReprogramming to Simultaneously Weaken Tumor Microenvironments andStrengthen the Immune Response
Enlivex’s lead drug candidate, Allocetra TM , wasdeveloped as an off-the-shelf cell therapy that reprogramsmacrophages , the immune cells responsible for killing infectedor harmful cells in the body. In cancer patients, macrophages oftenbecome reprogrammed out of their homeostatic state of relativelystable equilibrium so that they not only stop recognizing tumors asharmful but become weaponized by cancer to fend off other immune cellstrying to attack the tumor.
This reprogramming is a key mechanism of theresistance that cancer develops against immunotherapies. So the goalwith Allocetra is to introduce healthy donor cells that have beenmodified with an “eat me” signal on their surface to trigger thenon-homeostatic macrophages to engulf them. Once eaten, the donorcells are able to bring those macrophages back to a homeostatic state.
Early preclinicalresults show that this process, on a stand-alone basis, is enough toincrease survival duration and overall survival in mice with solidcancers similarly to current FDA-approved immune checkpoint inhibitors(anti-PD1 like Merck & Co Inc. ’s (NYSE: MRK) Keytruda,BMS’s Opdivo and Yervoy). But even more impressive was thesynergistic effect of administering Allocetra in combination withthese immune checkpoint inhibitors, which led to up to 100% completeremission of the cancer in the mice.
The Start of Human Trials Marks a Key Milestone inAllocetra’s Development
The next step for this new cell therapy is to testwhether these promising preclinical results will translate to humanstudies. This month, Enlivex initiated a Phase I/II trial to do justthat. After receivingapproval from the Israeli Ministry of Health in October,Enlivex begandosing the first patients in the trial in November.
The trial will enroll upto 48 patients with advanced solid tumors to evaluate the safety andtolerability of Allocetra as well as its preliminary efficacy, asmeasured by overall response rate and survival. Patients will bedivided into two groups – stage one and stage two – with stage onepatients receiving escalating doses of Allocetra as a standalonetreatment while stage two patients will receive three injections ofAllocetra combined with an anti-PD1 checkpoint inhibitor.
As Enlivex enrolls morepatients into the trial in 2023, it hopes to have top-line Phase I/IIdata by the second half of the year.
As part of a newgeneration of companies representing the future of cell therapy –off-the-shelf, highly scalable and low COGS “beyond CAR-T” celltherapies – Enlivex is focused on a highly differentiated novelimmunotherapeutic mechanism – macrophage homeostasis. Macrophagehomeostasis is severely disrupted by certain diseases states, and suchimbalance is critical to the progression of the diseases. Allocetrahas the potential to introduce highly-effective, low-cost allogeneiccell therapies for life-threatening clinical indications that aredefined as "unmet medical needs", including sepsis – one ofthe leading 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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