First Patients Dosed in Phase I/II Trial of Enlivex's Off-the-Shelf Cell Therapy Candidate, AllocetraTM

On November 13, Enlivex ENLV announced that the first patient has been dosed in its Phase I/II clinical trial of Allocetra. The novel off-the-shelf cell therapy is designed to help break through the immune-suppressing tumor microenvironment – a key roadblock rendering potent immunotherapies less effective against solid cancers – to render those tough-to-treat cancers more responsive to these treatments.

After a growing body of preclinical data demonstrated Allocetra’s potential to prolong survival duration and increase survival probability in mice, the Phase I/II studies are an important next step in evaluating their efficacy in humans.

Immunotherapies Tap the Body’s Own Cancer-Fighting Capabilities – But Solid Cancers Remain Resistant

As the field of immunotherapy makes strides, solid tumors continue to elude these novel treatments largely due to their complex and ever-adapting “tumor microenvironments.” These microenvironments leverage a range of immune-suppressing mechanisms that counteract the potent effects immunotherapies have had on skin and blood cancers. 

Chimeric Antigen Receptor (CAR)-T therapies, for example, have demonstrated a success rate as high as 90% for refractory B lymphocytic leukemia but as low as 17% for solid cancers. Novartis AG’s NVS Kymriah, the first CAR-T therapy to receive approval from the Food and Drug Administration, has since shown a durable remission and long-term survival rate, with as many as 55% of treated patients still alive more than five years later compared to the standard disease prognosis of 10% to 25%.

The reason for this difference is largely due to the range of mechanisms tumors use to resist or evade the immune system including disguising themselves as healthy cells, releasing immune suppressing signals, and blocking immune cells from getting into the core of the tumor. The more the tumor grows, the stronger these immunosuppressive mechanisms get – making it harder for the immune system to detect it. 

This makes tumors some of the least responsive cells to immunotherapies of all kinds as that microenvironment counteracts the effects of the treatment. Even in cases where tumors do initially respond to the drug, they adapt to resist it and the once-helpful immunotherapy is rendered ineffective. 

AllocetraTM Uses Cell Reprogramming to Simultaneously Weaken Tumor Microenvironments and Strengthen the Immune Response 

Enlivex’s lead drug candidate, AllocetraTM, was developed as an off-the-shelf cell therapy that reprograms macrophages, the immune cells responsible for killing infected or harmful cells in the body. In cancer patients, macrophages often become reprogrammed out of their homeostatic state of relatively stable equilibrium so that they not only stop recognizing tumors as harmful but become weaponized by cancer to fend off other immune cells trying to attack the tumor. 

This reprogramming is a key mechanism of the resistance that cancer develops against immunotherapies. So the goal with Allocetra is to introduce healthy donor cells that have been modified with an “eat me” signal on their surface to trigger the non-homeostatic macrophages to engulf them. Once eaten, the donor cells are able to bring those macrophages back to a homeostatic state. 

Early preclinical results show that this process, on a stand-alone basis, is enough to increase survival duration and overall survival in mice with solid cancers similarly to  current FDA-approved immune checkpoint inhibitors (anti-PD1 like Merck & Co Inc.’s MRK Keytruda, BMS’s Opdivo and Yervoy). But even more impressive was the synergistic effect of administering Allocetra in combination with these immune checkpoint inhibitors, which led to up to 100% complete remission of the cancer in the mice.

The Start of Human Trials Marks a Key Milestone in Allocetra’s Development  

The next step for this new cell therapy is to test whether these promising preclinical results will translate to human studies. This month, Enlivex initiated a Phase I/II trial to do just that. After receiving approval from the Israeli Ministry of Health in October, Enlivex began dosing the first patients in the trial in November. 

The trial will enroll up to 48 patients with advanced solid tumors to evaluate the safety and tolerability of Allocetra as well as its preliminary efficacy, as measured by overall response rate and survival. Patients will be divided into two groups – stage one and stage two – with stage one patients receiving escalating doses of Allocetra as a standalone treatment while stage two patients will receive three injections of Allocetra combined with an anti-PD1 checkpoint inhibitor. 

As Enlivex enrolls more patients into the trial in 2023, it hopes to have top-line Phase I/II data by the second half of the year. 

Image provided by Tima Miroshnichenko on Pexels

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