CAR-T therapies currently remain predominantly for use in oncology according to Chimeric Therapeutics CEO and Bioshares Biotech Summit keynote speaker Jennifer Chow.
Cancer therapies commenced largely in the 1940's with chemotherapy, which could be described as bombing the patient with broad acting drugs. This was followed by targeted therapies in the 1990's such as monoclonal antibodies. In the last decade, the major advances have been in immunotherapies, such as checkpoint therapies. These targeted therapies started to improve short-term survival, and then the immunotherapies were found to improve long-term survival.
In 2017, the innovation of the year in oncology circles was CAR-T cell therapy (Chimeric Antigen Receptor T cell therapy). What was unique about this therapy is that it was targeting both the tumour and the host simultaneously. It works by genetically modifying the T cells so that they can bind to and attack a specific type of cancer. All current CAR-T treatments are autologous, or personalised for each patient.
The process begins by taking a blood sample and transferring that sample to a manufacturing facility. From there just the T cells are isolated, which are then reprogrammed by inserting a new gene. The reprogramming then directs the T cells to find particular tumour cells. This occurs by the Chimeric Antigen Receptors becoming expressed on the T cells, said Chow.
The T cells are grown (expanded), frozen and then sent back to the patient for infusion, whereby they find and attach to the tumour cells. From there a signal is sent back to the immune system production centre to produce more of the same T cells. At this point cytokines are released by the body to kill those cancer cells. However, the T cells continue their work to find and destroy other of the same cancer cells.
The reason for the excitement was that one of the early patients treated with this therapy who was riddled with cancer cells became cancer-free at three months with a sustained effect also after 12 months of the single therapy.
In another patient with extensive, visible tumours (from double hit lymphoma), the 64-year old woman had failed every other available therapy. But just 10 days after treatment with CAR T cell therapy that Chow worked on, severe regression was visible, essentially 'melting away' the tumour. After 60 days, the tumours were completely gone.
Chow said that with CAR-T treatments, more patients are being kept alive over both the short and long term. The first CAR-T treatment was pioneered by Dr Carl June. The first two patients he treated were still alive after 10 years and CAR-T can now be considered a curative therapy according to Chow.
Chow said that the reason Chimeric Therapeutics was formed was to cure cancer through further development of cell therapies. There are six approved CAR-T cell therapies in the US (Kymriah and Yescarta approved in 2017, Tecartus, Breyanzi, Abecma, and Carvykti, which was approved this year). Chow has been involved in the development of four of those products.
However, at this point the only approved products are for the treatment of blood cancers. These products generate annual sales of US$2 billion, although analyst forecasts expect that to reach US$20 billion by 2029.
Challenges for CART-T
There are five key challenges in this field according to Chow. These are:
1. Applying the therapy to solid tumours
2. Managing adverse events (such as cytokine release syndrome)
3. Overcoming complex technical issues (relating to an autologous therapy)
4. Dealing with new commercial models, and
5. Sufficient experience and expertise in the field
Chow said the next step is to see similar results to what have been achieved in blood-based cancers, across to lung and brain cancers for instance. This is critical as 90% of all cancers are classified as solid tumours. The first challenge here is to make sure the therapy reaches the tumour. The second challenge is for these cell therapies to recognise the specific tumour cells. And the third challenge is for these therapies to not be inhibited by the immunosuppressive microenvironment of the tumour.
Chimeric Therapeutics is seeking to overcome the first of these challenges with its lead program by injecting the therapy directly into the brain cavity (in fact the first cohort of patients received injection directly into the brain tumours). This first therapy is targeting CDH17 which is highly expressed and needed for tumour formation. With the company's CORE NK technology, Chimeric Therapeutics is adding enhancements to fight the innate immunosuppressive tumour resistance (such as Il-15 and TGF-Beta).
Chimeric Therapeutics is starting to see some effect at early stages, albeit still at very low doses, with disease stability in 70% of patients where the therapy is being injected.
Managing Adverse Events
The three 'notorious' averse events linked to CAR-T cell therapies are cytokine release syndrome (CRS), neurotoxicity, and on target - off tumour toxicity. Over the last five years, very good progress has been made in managing the first of these two side effects, which occur in 10%-30% of patients. This is through identifying at-risk patients and administering prophylactic or responsive treatments, as well as modifying the therapeutic load.
For managing the third risk, in is crucial to choose the right targets as the CAR-T will also kill the healthy cells if the target is expressed on those cells as well as the tumour cells according to Chow.
Chimeric Therapeutics' CDH17 CAR-T was partially invented by Dr June as well as Dr Xianxin Hua. Over 10 years was spent optimising the different parts of this CAR-T therapy. A lot of work went into ensuring no damage was done to healthy cells in animal models.
Technical Challenges
The main risk for companies in the CAR-T space according to Chow is not clinical development (which is the case with many other drugs in development) but in making sure the technical operations are coordinated correctly.
One example Chow cited was a UK company Autolus, which Chow said was founded by a brilliant scientist. Early data showed an impressive 73% complete response rate, which compared to a 50% response rate with Yescarta, which Chow was working on at the time. The Autolus CART-T program was targeting two tumour receptors, CD19 and CD20. However, after manufacturing setbacks, the company reduced its workforce and sidelined the asset. At the time it was thought this asset was going to dominate the CAR-T market said Chow.
Another example of not correctly addressing the technical challenges was one of the two CAR-T programs gained by Bristol Myers Squibb from its acquisition of Celgene. Due to manufacturing delays, Celgene shareholders missed out on a US$6.4 billion 'Contingent Value Right' payment when the therapy wasn't approved by the deadline at the end of 2020. That therapy was subsequently approved and is called Breyanzi.
Simplifying CAR-T
To reduce the manufacturing challenges with CAR-T (as well as delivering a more accessible and less expensive therapy), Chimeric Therapeutics is working on an allogeneic (off-the-shelf) therapy where the cells come from the one donor (its CORE NK technology). Chow said that the company has already seen incredible results from this technology in blood-based cancers (100% disease control rate and more than 15 months complete response achieved). In solid (more challenging) cancers, the disease control achieved to date with the allogeneic therapy has been 33%.
The new commercial model for CAR-T, which is a once-off treatment, means that the cost is very high, between US$373,000 - US$475,000 for three of the leading therapies. However, this compares well to the price of annual treatments with other drugs for similar indications. Another challenge for CAR-T adoption is explaining to patients and the medical teams the additional considerations, including manufacturing times for the individualised therapy. Patients also need to be two hours from the treatment centre as well as having a nominated caregiver.
Given the explosion of interest, another issue has been developing the expertise in CAR-T. One of the important assets of Chimeric Therapeutics is its experienced team. Whilst only comprising of six people, those six staff have over 50-years experience in this field stated Chow.
Chow finished with summarising Chimeric Therapeutics' exciting position in the field. The company has positive results from two clinical studies (glioblastoma in the autologous therapy and in blood and solid tumours with its allogeneic therapy), and seven discrete assets that are tackling more than 10 disease areas. The company plans to have eight clinical programs underway by next year.
Bioshares recommendation: Speculative Buy Class B
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