Traditional cancer treatments tend to be unprecise, the effect of which both healthy and cancerous cells are destroyed. Chemotherapy or radiation are like the military carpet bombing an area, and often cause considerable collateral damage. Additionally, traditional therapies have significant limitations in treating certain cancers and other genetic disorders. This has led to the development and implementation of an entirely new therapy class, known as advanced or regenerative therapies. One subtype of these therapies is a CAR T-cell therapy.

What is a CAR T-cell therapy? In short, it is collecting, separating, and re-engineering a patients’ own immune cells to identify and then attack their cancer or other affliction. The goal of Chimeric antigen receptor (CAR) T-cell immunotherapy is to modify a patients T-cells to recognize cancer cells so that they can seek out and destroy them. Doctors harvest T cells from the patient, genetically alter them, then infuse the resulting CAR T-cells back into the patient to attack their tumors. CAR T-cells can be harvested from T cells in a patient’s own blood (autologous) or derived from the T cells of a healthy donor (allogeneic). Both autologous and allogeneic CAR T therapies enable the immune system to attack only cancer cells and leave healthy cells unharmed.  One of the many advantages CAR T has over traditional treatments is that the therapies are administered over a short period of time with the goal of curing the disease rather than managing it. Early results demonstrate a significant and often curative result against hematologic cancers. There are two main side effects: cytokine release syndrome (CRS), affecting about 70-90% of patients; and, CAR T-cell-related encephalopathy syndrome (CRES). Either can start relatively soon after the treatment however, both have short durations and in the case of CRES (confusion and sometimes not being able to speak at all for a few days) are reversible or short-lived.

In 2017, the FDA approved the first two CAR T therapies, one from Novartis, Kymriah (read more) and one from Gilead/Kite, Yescarta (read more).

Given the early success of these two therapies, up to 94% remission rates in some cases, it is not surprising that there are currently over 240 active CAR T therapy clinical trials (read more). Both Kymriah and Yescarta are approved for targeting cancers that are hematologically based.  However, with new advances in biology and technology, scientists are starting to look at and target solid tumors, despite the inherent difficulties in employing CAR T therapies against solid tumors including tumor infiltration and addressing the tumor micro-environment, which can be detrimental to CAR T treatments. Applying CAR T treatments to much more common, and more commonly fatal, solid tumors is exciting and demonstrates that the space is not stationary and is advancing to address a wider application base in medicine. In fact, Gilead/Kite, on the back of the success of Yescarta, have been moving forward with a Phase III trial targeting solid tumors (https://clinicaltrials.gov/ct2/show/NCT03391466).

TC Biopharm has two preclinical projects targeting solid tumors.  One targeting lung, breast, colorectal, liver and skin cancers; and, one targeting breast and ovarian cancer.  There are 270,000 new cases of breast cancer and 23,000 new cases of ovarian cancer per year in the United States alone. Another company investing heavily in finding effective CAR T therapies for solid tumors is Celyad. Celyad has reported some early success in trials targeting Colorectal cancer. These are just a few of the many examples of companies looking to expand the application of CAR T therapies as the science advances.
      
A CAR T therapy is effectively a living drug. Each patient is unique, with many having compromised immune systems, or being inherently unstable and the quality of starting material is a key consideration that directly relates to the success or failure of a given cell therapy treatment regimen. Moreover, building out manufacturing capabilities to meet the variability from patient to patient, lot to lot, is a pressing and ongoing challenge. Building manufacturing capabilities for Phase I studies with less than 20 patients is not yet putting too much stress on the global cellular manufacturing capabilities. However, as therapies targeting large patient populations move through the drug development life cycle, overall contract manufacturing capacity and facility availability is going to be limiting and remains a critical consideration for biotechnology companies. 

In addition to the manufacturing process, the ability to ensure Chain of Compliance across the supply chain is an absolute necessity. Chain of Compliance, being similar to cGMP traceability standards in a manufacturing environment, will provide the additional safety and visibility these therapies require while in transit. Understanding how and what temperatures these therapies need to be transported to and from the point of care to the manufacturing site and back to the point of care is one of the unique challenges facing these companies. In many cases, these therapies are a patient’s last hope of receiving an effective treatment for their disease. Clinical studies have quickly shown whether a therapy is going to be safe and effective. Building out supply chain competencies may become the limiting factor when thinking about the addressable patient population.

Based on the number of IND’s currently on file, it’s highly likely that many of these therapies will be approved in the coming years. Former FDA Commissioner Scott Gottlieb anticipates more than 200 Investigational New Drug applications per year by 2020 for cell and gene therapy candidates. Based on those numbers, the FDA predicts, 10 to 20 approvals each year for these treatments by 2025 (read more). As a result of this forecast, the FDA has hired or will be hiring an additional 50 CAR T-specific reviewers.

Finding a safer, more effective treatment for these conditions will be life changing for these patients and their families. An important take away is that with companies focusing on solid tumors, patients who only had ~six months left to live now have a possible alternative at a life-saving or life changing treatment.