Shooting for 95%

We have created a nanotechnology based cancer therapy that we believe is capable of delivering a 95% response rate to solid tumor cancer patients. Why are we so confident? Because it’s already been done.

SOME BACKGROUND

A characteristic of the micro-environment in all solid tumors, and a primary driver of cancer therapy failures, is high tumor fluid pressure. As a tumor grows, high fluid pressure surrounds cancer cells and pushes anti-cancer agents toward the tumor’s periphery.

High fluid pressure in solid tumors is a consequence of the unique, malformed nature of tumor blood vessels. Tumor blood vessels contain small gaps (200nm to 1200nm) called fenestrations.

These small gaps allow excess fluid and blood components to flow into a tumor’s interior, pressurizing it like a water balloon. The effectiveness of solid tumor therapies, including chemotherapy, radiation therapy and  immunotherapy, are limited by the high fluid pressure in the tumor micro-environment.

ELIMINATING HIGH FLUID PRESSURE INSIDE TUMORS

A reasonable approach to improving cancer treatments is to disrupt the high pressure gradient inside solid tumors by destroying the tumor blood vessels that feed the tumor’s high pressure gradient. A class of molecules called vascular disruptions agents (VDAs) can destroy tumor blood vessels. Unlike anti-angiogenesis medications such as Avastin, which prevent NEW blood vessels from growing into tumors,  VDAs destroy existing tumor blood vessels. This leads to a rapid elimination of high tumor fluid pressure. No VDA has been approved for SYSTEMIC USE in cancer patients because VDAs are too toxic. However,  we do KNOW the therapeutic approach works!

A TEMPLATE FOR HIGH RESPONSE RATES

An immune system molecule called Tumor Necrosis Factor Alpha (TNF) is a potent VDA. TNF is currently used in Europe as part of an approved clinical procedure called Isolated Limb Perfusion (ILP). In this procedure, the blood vessels on a tumor-bearing  arm or leg are isolated from the rest of the body’s circulatory system using a heart-lung machine. A physician then injects TNF into the isolated limb. TNF reaches and begins destroying tumor blood vessels in a matter of minutes. The patient is then given  a high dose of standard-of-care chemotherapy. Tumor response rates as high as 95% have been reported from European clinics using the  ILP procedure. This is far greater than what is typically observed with chemotherapy alone. The procedure is typically performed only once due to the heroic nature of the surgery. (Note: Average response rates vary by study, but the majority of multi-center studies report greater than 80% response rates with a single treatment)

UNDERSTANDING TNF

TNF Alpha was discovered and isolated more than three decades ago. It is a multi-functional immune system signalling molecule that can cause both cell death and cell proliferation (see diagram below). Blood vessels that grow into solid tumors  have a higher than normal number of TNF receptors on their epithelial cells, which are the cells that make up tumor blood vessel walls.

When TNF binds the receptors on tumor blood vessel epithelial cells, many of these cells under go a process called Apoptosis, or cell death. For this reason, the TNF receptor is also known as the “death receptor.” When blood vessel epithelial cells die, we can observe a “vascular bleed.” This is when massive holes in the tumor’s blood vessels allow red blood cells and other blood components to pour into the area around the damaged blood vessels.  After exposure to TNF, tumor blood vessels are quickly destroyed, which prevents fluid from being pumped into the interior of the tumor. Cutting off the fluid flowing into the tumor’s interior eliminates the tumor’s high fluid pressure. This has two relevant clinical effects, which are seen in the tumors of patients undergoing the ILP procedure, and which we have demonstrated in numerous animal studies:

  1. The tumors interior becomes necrotic (dies) from lack of oxygen and nutrients.
  2. As the tumor’s high fluid pressure drops, the surviving cancer cells are exposed to an increasing amount of chemotherapy, which results in a dramatically better clinical outcome.

TURNING ISOLATED SUCCESS INTO SYSTEMIC SUCCESS

CytImmune created the Aurimune nanomedicine platform to systemically delivery  TNF. The first generation Aurimune nanomedicine, CYT-6091,  can selectively deliver TNF to primary and metastatic solid tumors in approximately the same dosage as is used in the clinically approved ILP procedure. Preclinical data has been collected in more than a dozen solid tumor mouse models. This data has demonstrated that the TNF attached to CYT-6091 is biologically active when it reaches the tumor. That means we can observe a vascular bleed in tumor blood vessels, and we see the expected elimination of high tumor fluid pressure.

Response rates in clinically predictive, genetically engineered mice that get pancreatic cancer tumors, when Aurimune is followed by chemotherapy, are consistent with the success seen in the ILP procedure.

CYT-6091 has been tested in a Phase 1 clinical trial with advanced stage cancer patients. Numerous tumor types  were represented in the clinical study. This included tumors of the breast, lung, pancreas and colon. Tumor types included: sarcoma, adenocarcinoma, and sarcoma. No serious adverse events and no dose limiting toxicity were observed, despite the administration of 3x the previous maximum tolerated dose of TNF. Unlike the ILP procedure, which can only be performed once, patients will be able to repeatedly receive TNF carried by our CYT-6091 nanomedicine. And since the blood vessels feeding  a patient’s tumor(s) are not themselves cancerous, we do not expect to see traditional resistance develop to CYT-6091.

We know TNF combined with chemotherapy can achieve a 95% response rate in limb tumors treated using the ILP procedure. CytImmune is working to bring that high response rate to all solid tumor cancer patients.

 

*We  encourage patients and advocates to ask questions. You may enter questions in the comments section of this post, or reach out to us on Twitter, @CytImmune.

**Since CYT-6091 is a clinical stage product, we are unable to provide treatment outside of a clinical trial.

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