One of the chief challenges cancer researchers face today is finding a way to outsmart the disease’s defense mechanisms. Because the cancer isn’t an infection but a mutation of the patient’s own cells, it has a unique ability to evade attack from the immune system, both by hiding from it and by suppressing it.
This has reportedly made immunotherapies some of the most promising new cancer treatments doctors have today. Anti-PD-1 therapies like Merck & Co. Inc.’s MRK Keytruda and anti-CTLA-4 therapies like Bristol-Myers Squibb Co.’s BMY Yervoy each block different “off switches” cancer cells use to tell the immune system to leave them alone. These three drugs had 2021 aggregated sales of approximately $22 billion in 2021.
As good as these drugs are, they offer relatively small efficacy fo rthe majority of solid cancer patients, with survival probability for many patients is in the low 20%, somewhat of a glass ceiling of survival that does not seem breakable with available therapies today.
Enlivex Therapeutics Ltd. ENLV, an Israeli-based clinical-stage pharmaceutical company, says it wants to help these leading drugs to break that glass ceiling and increase significantly survival rates of cancer patients by developing a highly differentiated immunotherapy that would be used in combination with the leading drugs. The company explains that the concept is restoration of anti-cancer equilibrium to the immune system which would dramatically increase the effectiveness of the anti-cancer drugs.
What Are Macrophages?
Macrophages are the immune system’s first responders when fighting a disease. Circulating throughout the bloodstream and tissue as monocytes, these immune cells can transform at the first sign of infection into macrophages.
Once transformed, they engulf the pathogen, rip it apart and send out alarm signals that activate other parts of the immune system like T cells. They also produce both inflammatory and anti-inflammatory factors to regulate the body’s immune response, including elimination of cancer cells.
In this role, they essentially act as patrol and chief regulators of the immune response from start to finish — constantly on the lookout for possible pathogens and sending out signals to start and stop the inflammatory response.
The Role Of Macrophages In Combating Disease
That important role makes them an essential tool for protecting the body but it also means any disruption or hiccup in their function can have a huge impact on the immune system’s ability to fight disease.
In cancer, the disease can evade the immune response by sending out “don’t-eat-me” signals that trick the macrophage into believing the cancer cell is actually a normal, healthy cell. It also converts macrophages into tumor-promoting allies by reprogramming them to suppress any incoming immune responses that could kill the cancer cells.
As a result, these dysregulated macrophages may not only fail to identify cancer cells as a threat but might even help create an environment where the cancer grows more easily — and where immunotherapies like checkpoint inhibitors can have limited impact.
How Enlivex Reports Reprogramming Macrophages To Fight Cancer
While dysregulated macrophages can be manipulated into creating the optimal environment for cancer to grow, properly functioning macrophages may have the potential to launch a powerful attack against that same cancer.
That unique situation is what the team at Enlivex says led it to explore ways to get inside a patient’s macrophages and reprogram them to resist cancer’s tricks. The hope is that restoring the balance would not only weaken the cancer by removing one of its best defense mechanisms but also strengthen the body’s own ability to fight the disease.
The clinical-stage pharmaceutical’s lead drug candidate Allocetra might be able to do just that.
The cell therapy uses cells filtered from blood donations of healthy volunteers, and processes them through a proprietary process. Once these modified cells are infused into the patient’s system, they send out an ‘eat me’ signal that tells the patient’s own macrophages to engulf the Allocetra treatment.
After being engulfed, Allocetra can restore equilibrium to the macrophage, allowing it to recognize the cancer as a disease and launch the appropriate immune response.
In one study that the company conducted in collaboration with the Yale Cancer Center, when Allocetra was combined with an anti-PD-1 inhibitor similar to Keytruda, for example, mice with ovarian cancer that were treated with anti-PD-1 alone had a reported 10% survival, while the combination treatment saved 50% of the mice.
Similar improvements were seen in a preclinical study pairing Allocetra with an anti-CTLA-4 inhibitor similar to Yervoy to treat mesothelioma, a very aggressive cancer. Between 60% and 100% of mice receiving the combination therapy saw complete cancer remission and survival, depending on the dose received, while the untreated group had 0% survival, and anti-CTLA-4 stand-alone provided 25% survival.
Building on that data, Enlivex states it is has recently received regulatory approval to initiate a Phase I/II clinical trial in patients with advanced-stage solid tumors, that will receive combination treatment of Allocetra and chemotherapy, and is planning an additional Phase I/II clinical triall later this year in patients with advanced-stage solid tumors that have low survival probabilities, treating with the anti-PD-1 and Allocetra combination.
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