A paradigm shift is in full swing when it comes to cancer treatment... while radiation and chemotherapy most widely used (along with surgery for solid cancers), or bone marrow transplants have been the 'last hope' for those who have had their immune systems destroyed from chemotherapy/radiation.... we have only recently entered a new age of cancer treatment with Chimeric Antigen Receptor (CAR) T cell (T) therapy.
To date, CAR-T therapy has shown itself to be extremely effective in treating blood based cancers.
July 24 2020 mantle cell lymphoma (blood cancer) - Brexucabtagene autoleucel (Tecartus) arises in B cells (white blood cells), 60 patient trial who were refractory (received at least 5 prior treatment) 87% response rate, and 62% were disease free. Three of the 60 patients died of side-effects, which the FDA deemed for patients with mangle cell lymphoma would be a tolerable level of risk given they would not have been expected to survive for another year.
Other FDA approved CAR-T treatments include:
Tisagenleceucel (Kymriah) for diffuse large B-cell lymphoma and acute lymphoblastic leukemia Axicabtagene ciloleucel (Yescarta) for diffuse large B-cell lymphoma. Lisocabtagene maraleucel (Breyanzi) for large B-cell lymphoma
With only four approved treatments at the start of 2021... this field is set to explode in the coming years.
While CAR-T therapy has shown extraordinary results for blood based cancers, there has been very limited success when it comes to solid cancers such as Glioblastoma (GBM) which grows in the brain or spine, melanoma, prostate cancer, lung cancer, and sarcoma.
Solid cancers pose a different challenge when compared to blood based cancers. CAR-T therapy is a bit like a puzzle... if you find the right piece for that specific cancer (puzzle), you have a chance at breaking down (solving) that specific cancer. These puzzle pieces are called receptors/antigens, and the goal is to find a receptor on the surface of a cancer cell that is unique to that cancer so that a synthetic antigen puzzle piece (CAR) can be created for the patients T cells to then home to, bind, multiply and destroy that cancer.
CAR-T therapy has shown success with blood based cancers which have such an receptors expressed on the B-cell surface called CD-19. I believe all the FDA approved treatments target this specific antigen.
CD-19 is expressed (present) on blood based cancers, but not in healthy cells.. which means there is less chance of the immune system destroying healthy cells. However the risk of cytokine storms and/or neurological disorders still exist.
Solid cancers have to date been a much more difficult challenge, and I'm not scientist so I'm really simplifying the challenges here, but one of the key challenges (but by far not the only one), solid cancer cells are not uniform and more importantly... they have the ability to adapt/evolve as it grows and spreads through your body/brain.
Researchers to date have tried a similar approach to that of treating blood based cancers (given their success), however with the limited number of antigens expressed in solid cancers such as GBM .. when these were targeted (e.g. EGFRvIII and IL13Rα2) with CAR-T therapy, the solid cancer would only show a small decrease in size where these receptors were successfully targeted and lead to the destruction of those specific cancer cells. However, the solid cancer would simply grow back with less or no EGFRvIII and IL13Rα2 receptors... meaning the CAR-T therapy developed to treat the solid cancer was no longer effective. This is called antigen escape, which this highly evolved enemy has up its sleeve and has so far eluded anything and everything thrown at it by modern science...
In steps Chlorotoxin (CLTX)-CAR T, Chimeric Therapeutic's (CHM.ASX) novel treatment to tackle solid cancers. It has previous made headlines as the puzzle piece (Chlorotoxin) used in this CAR T is sourced from the venom of the death stalker scorpion. So what makes CLTX so unique and special? To appreciate it, we have to look at the existing CAR-T therapies that have used an antigen that targets a single reception on a cancer cell, such as CD-19 mentioned above. These approved treatments are known as first generation CAR-T treatments, which are relatively simple (relatively to CAR-T therapy, which is not simple at all!) as it is based on a single targeted receptor.
Chlorotoxin (CLTX) is a naturally occurring 36 amino acid peptide, which has been used as the puzzle piece attached to a patients T cells. So rather than fully synthetic puzzle piece... the researches at City of Hope used a complex naturally occurring puzzle piece.
Why is this significant? Firstly, CLTX has shown to be able to bind to solid cancers like GBM extremely well. Pre-clinical studies show that most patients have more than 80% binding, with only 2 out of 25 tumors showing less than 40% binding. This shows that CLTX binds to a broad spectrum of GBM cancer cells, that is it binds to more than one type of receptor.... a master puzzle piece if you will. While the exact receptors CLTX are able to bind to are still unknown, City of Hope researchers have found that there is a relationship with member protein MMP2, however this relationship will need to be further examined in future clinical trials.
So how did they come to use CLTX in a CAR-T therapy? Fluorescent labeled CLTX was previously used to highlight tumors for surgery, which City of Hope researchers thought could mean that it would be a great homing device for a CAR-T therapy. This also means that CLTX is not a new agent used in the field of medicine, and it has been proven to be safe when injected into humans, including in the human brain.
All of this bodes well in terms of CLTX CAR T's potential safety and efficacy profile. Where there a less than 5% survival in GBM patients after 5 years, any benefit in survival will mean that GBM sufferers can have genuine hope that their diagnosis is not a death sentence. Moreover, and for another day... CLTX has shown that it binds very well with a wide range of solid tumors... not just GBM. So if the phase I trial is shown to be safe, and signs of efficacy are evident... then this treatment is likely to be approved through a small phase II trial (which was the case with currently approved FDA CAR T Therapy), and big pharma will no doubt view this as a major major breakthrough... and as I type this, CHM.ASX is under A$100m market cap.
It's been a little quiet for this newly listed ASX company.. and I don't normally do this... but I'm really interested to get the thoughts of some other great posters on HC and hopefully stimulate some constructive discussions to broaden the knowledge of all investors at this very early stage CAR-T play (Phase I). Probably missed a lot of quality contributors, but off the top of my head:
(20min delay)