The Quest for a Functional Cure in Cancer Reaching an Inflection Point

The recent clinical trial data announced by CytoDyn Inc. (OTC.QB: CYDY) was highly supportive toward their Breakthrough Therapy Designation (BTD) filing for Metastatic Breast Cancer (MBC) made on January 13, 2020.  Cancer metastasis is responsible for about 90% of cancer deaths so any treatment that can make a universal impact on stopping the spread of cancer is welcome. Cancer has many defense mechanisms and among them is suppression of the immune system.  Immuno-Oncology (I-O) is about finding ways to target and control the immune system to eliminate cancer. The first major breakthrough in I-O was the checkpoint blockade which prevented existing T-Cells from triggering their own death thereby suppressing the immune system.  This led to the widespread use of drugs like Keytruda, Opdivo, Yervoy, Imfinzi, Bavencio, and Tecentriq. The next evolution in I-O appears to stop the trafficking of suppressor cells to the tumor microenvironment (TME) neutralizing cancers most offensive weapon called metastasis. This is where CYDY is playing a key role into what may ultimately result in a functional cure for metastatic cancer.  

Targeting the Primary Tumor vs Metastasis

For decades almost all cancer treatments have revolved around reducing the primary tumor.  The success of a treatment regimen was how much a drug, surgical procedure, or radiation reduced the size of the tumor over time.  CYDY took a novel approach and targeted metastasis itself and got into defining what caused metastasis. Metastasis comes from a primary tumor that sheds clusters of cells, called Circulating Tumor Cells (CTCs), into the bloodstream that eventually take root in an organ and begin to grow.  These CTCs are shed into a very hostile environment called the circulatory system, and cannot survive more than a couple of hours before the immune system sees the CTCs and destroys them. The problem is that metastasis is a numbers game. The more CTCs a tumor sheds the worse the prognosis. So even treatments that showed large tumor reduction didn’t always result in a durable response.  The key to a functional cure in cancer is stopping the metastasis. So anything that targets CTCs would be a powerful neutralizer of cancers most offensive weapon. 

Understanding Metastasis

Metastasis is the process by which cancer cells break away from the primary tumor and spread through the bloodstream or lymph system to other parts of the body.  There are a couple of parts to metastasis.  

The first part is that the tumor cells fight their way into the vasculature then they swim around looking for a place to roost while the immune system is hunting them down.  Once they found a spot in an organ the second thing they need to do is fight their way through the capillary walls and invade into the tissue. Once these cells have found a spot the third thing they do is multiply and try to trick the body into growing new capillaries to feed the growing tumor.  Once the tumor reaches a certain critical mass the fourth thing it does is create stromal cells around the tumor that act as a protective shield from the immune system. 

How Leronlimab Neutralizes Metastasis

The understanding of the mechanism of action (MOA) of leronlimab is still evolving as patients continue their clinical trial.  The first step in the metastatic cycle is the shedding of CTCs. Once these CTCs are shed they need to muscle their way into the circulatory system. Actin filaments are basically the structure inside the cells that keeps cells bound to each other.  Actin filaments are located on the periphery of the cell and help shape a cell and determine the stiffness of the cell surface.  These actin filaments are extremely sensitive to calcium signaling.  CCL5 is what signals calcium and collapses the physical structure of the cells allowing the cancer cells to migrate and squeeze between the capillary (endothelial) cells and reach the bloodstream.  By blocking CCR5 lenronlimab is adding to the size and structure of the cancer cell and preventing it from squeezing through into the blood system. This is the first way that leronlimab stops metastasis by not even allowing the CTCs to escape and invade into the blood system.

The largest effect that leronlimab has on the primary tumor is that it stops the trafficking of CD4 suppressor cells to the tumor microenvironment (TME).  Stopping the movement of suppressor cells to the tumor microenvironment allows existing immune cells to continue to fight on. The body is always trying to maintain balance in the immune system which is why we have regulatory and suppressor cells.  Leronlimab tips the scale toward a more active immune response. Stopping this migration also leads to a reduction of tumor volume as evidenced by a 20% reduction in tumor size in one patient just weeks after injection. 

Coronavirus Application: What is so interesting about this specific MOA is that stopping the trafficking of suppressor cells is also the key to fighting viruses.  After the initial viral infection the adaptive immune system takes over to restore balance and it sometimes kicks into gear too early. If you ever had a virus and started to get better but just couldn’t get over the hump, those are your suppressor cells at work. 

The drug has also shown that it has an anti-angiogenesis effect.  Angiogenesis is the pathway in which new blood vessels are sculpted.  Imagine roots in the form of blood vessels sprouting from a capillary or artery.  The tumor tricks the body into nourishing it through the CCL5 pathway.  Depriving the tumor of oxygen and nutrients is another way to combat cancer. 

Exploring a Functional Cure without Surgery  

Many people have tumors on their body and they are considered benign.  For those with benign tumors they are left alone unless they interfere with a patient’s function.  These types of benign tumors don’t spread because they are encapsulated.  This is a lead into what a functional cure would look like. It’s a situation where you have a cancerous tumor, but don’t have to worry about cancer spreading to other parts of your body.  It’s localized and can be watched, it’s not growing or if it is growing it growing at a very slow rate. Early preliminary clinical trial results are very encouraging, and demonstrating that lenronlimab might be a functional cure for metastatic cancer.  Preliminary clinical trial results have been able to demonstrate that CTCs levels go down to zero after a couple of weeks of treatment and stay there.  The drug has also demonstrated tumor shrinkage within a couple of weeks. The concept behind leronlimab is that it stops the spread of cancer dead in its tracks.  Surgical removal of a tumor is also a functional cure because if they get it all out it won’t spread. Surgical cures are only available for cancers that haven’t metastasized. 

If cancer doesn’t grow and doesn’t spread it ultimately doesn’t represent much harm; very much like benign tumors.  Leronlimab is shaping up to be the first truly functional cure for metastatic cancer because the treatment involves injection of a non-toxic monoclonal antibody that puts the cancer’s growth in stasis.  If the results from these clinical trials continue to be confirmed cancer may have finally met its match. 

Trial Results and Breakthrough Therapy Designation

A summary of the trial results was released on February 14, 2020 and showed that 3 out of 4 patients had zero circulating tumor cells.  The fourth patient had high levels and after just two weekly treatments showed a significant reduction. Only two of the patients that were measured for tumor shrinkage shortly after treatment.  Both showed tumor reduction, but the patient with the more pronounced disease, taking the higher dosage, showed 50% tumor reduction at 3 weeks and another 55% tumor reduction after an additional 3 weeks for a cumulative tumor reduction of approximately 80% after 6 weeks. Anecdotally this formerly bedridden patient was able to resume normal activity within a very short period of time allowing for a much better quality of life. 

Results like these appear to meet the requirements of Breakthrough Therapy Designation (BTD).  In order to get BTD the drug must be targeting a life threatening disease and have clinical evidence in human trials that it may demonstrate a clear advantage over available therapy.  CELLSEARCH is an FDA approved test to measure CTCs and has been mainly used since its approval in 2004 as a prognostic tool. There are few if any clinical trials using CTC’s as a surrogate endpoint because until leronlimab, metastasis simply was not targeted.  Three major studies in breast, prostate, and colon cancer show the clinical benefit of reducing CTCs under 5 and keeping them there.    The incredible safety profile of leronlimab in 840 HIV patients is another testament and reason why it will not be difficult to award BTD to leronlimab.  Right now many patients who have cancer metastasis have no treatment options and will die if they don’t get treatment. It is unfathomable to think that leronlimab, the perfect definition of a breakthrough therapy drug will not get the designation.  The true debate will be centered on whether or not the FDA is willing to grant conditional approval before the required regulatory response due date on March 14th.              


CytoDyn is a rising leader in the I-O market and their lead drug candidate leronlimab has the potential to reshape the space with a functional cure for metastatic cancer.  Time will tell, but this drug could outsell top selling drugs like Keytruda, Opdivo, and Tencentriq manufactured by Merck (MRK), Bristol Myer-Squibb (BMY), and Roche (RBBHY).  What is so interesting is that this drug is likely to be synergistic with other I-O drugs making this the most prized possession in a combination cancer therapy. Leronlimab could be the first line treatment of cancer upon diagnosis while its imaging is studied.  This could ultimately move cancer away from cancer specialists, and put treatment in the hands of the general practitioner. Imagine a world where your doctor diagnoses you with cancer matter of factly, and prescribes you with a weekly injectable like what diabetics take until they do so imaging and see how well your tumor is shrinking without experiencing any toxic side effects.  This could be a reality in as soon as 30 days but what is hardest to fathom about this story is how the company with full rights to leronlimab and a potential functional cure for metastatic cancer is currently worth only $600 million.