Developing CAR-T cell therapies for the future

The article notes that the development of chimeric antigen receptor (CAR) T cell therapies has been a cause for excitement and celebration amongst researchers and patients within the oncology space because of their ability to eradicate advanced forms of leukemias and lymphomas. It was Yoshikazu Kurosawa, a Japanese immunologist, and his team who initially reported on the concept of chimeric T cell receptors in 1987. However, it wasn’t until 30 years later, in 2017, that the first CAR-T cell therapy was approved by a regulatory body—FDA approved tisagenlecleucel (Kymriah, Novartis) for the treatment of pediatric and young adult patients with a form of acute lymphoblastic leukemia.

Since the initial approval of tisagenlecleucel, there have only been a limited number of other CAR-T cell therapies that have successfully completed the regulatory review process. Challenges hindering growth of the CAR-T cell therapy sector have included the COVID-19 pandemic—which resulted in a low diagnosis rate of blood cancer, disrupted supply chains, and difficulties in monitoring patients closely—and the expense of developing the therapies and cost per treatment for the patient.

Paolo said: “The development of CAR-T therapies is a complex, costly and time-consuming endeavor, which requires specific expertise across a number of scientific disciplines as well as competencies from a regulatory, commercial and bio-manufacturing perspective. There are currently only six CAR-T therapies available on the market: all of these are autologous (i.e., personalized therapies) and target hematological malignancies, such as acute lymphoblastic leukemia, multiple myeloma, and B-cell lymphoma.”

Key considerations

He continues: Generally-speaking, CAR-T cell therapies either in development or those approved and commercially available came out of academic medical centers or biotech companies, Siciliano continues. Big Pharma companies have a tendency to take ownership during the development and commercialization stages. "Very few organizations have the capabilities and expertise in-house to bring a CAR-T therapy from idea to market by themselves, and finding the right partner at the right time of the development process is key to reduce risk and increase the likelihood of the therapy to make it to the market.”

When approaching development of a CAR-T cell therapy, there are some key considerations to take into account, and these can be grouped by the development stages, Paolo notes. In the preclinical research stage, it is important to consider the selection of the therapeutic area of interest, the right target (cell and antigen), and the vector/platform for gene transfer. It is also crucial to balance potency and safety through affinity optimization, minimizing potential off-target effects.

Moving along to the clinical study stage of development, Paolo continues, the following need to be carefully thought about: clinical trial design; selection of locations/partnering medical centers; patient enrollment; safety and monitoring; data analysis; and compliance with regulations. Then in manufacturing, companies need to determine the manufacturing processes and technologies, as well as whether to manufacture in-house or via an outsourcing partner, while also defining the logistics and supply chain, ensuring compliance with regulations, and implementing quality control procedures and processes. Finally, for commercialization, regulations again play a significant role as companies need to make sure they are fully compliant, and they must also figure out the most appropriate market strategies and what the pricing might be or whether there will be any potential reimbursements available as these factors can have profound impact on patient access to these therapies.

Constant growth

Paolo adds: “Despite a relatively slower 2023, the CAR-T and [overall] cell and gene therapy (CGT) industry has been seeing constant growth over the past few years since the first approval of a CAR-T therapy in 2017, with increasing investment, R&D, technology development and M&A activity.” Providing some examples, he reveals that there has been greater collaboration between academia and pharma/biotech, more knowledge about therapy development and manufacturing, and increased access to good manufacturing practice manufacturing facilities, boosting the preclinical and clinical therapy development sectors. Further along the development lifecycle, in manufacturing and supply chain, he highlights the fact that there are more contract development and manufacturing organizations providing capacity for CAR-T and CGT drugs, more collaboration across the ecosystem, innovation in CAR-T manufacturing technologies, and greater interest in digital, automation, and advanced technologies such as artificial intelligence. “[Furthermore], key regulations are undergoing harmonization across regulatory agencies globally, and there are increasing levels of expertise in regulatory pathways for CGT and CAR-T therapies across the industry. And in commercialization, [there are] new reimbursement models being tested and an increasing number of countries approving and adopting CAR-T.”

Future expectations

Paolo continues: “The field of CAR-T therapies is likely to see considerable advancements over the next decade. Anticipated advancements include, for example, the broadening of therapeutic targets—such as using CAR-T for solid tumors, expansion into non-oncology indications, such as autoimmune diseases, new molecular and technological approaches that reduce manufacturing times of autologous CAR-T therapies, new molecular mechanisms that enhance safety through improved specificity and efficacy, harmonized regulatory pathways, and new payment and reimbursement models." Additionally, the industry will benefit from new genetic transformation technologies. “In 2023, [there has been] the first approval of a CRISPR [clustered regularly interspaced short palindromic repeats]-mediated genetically modified cell therapy,” he says. “New approaches to gene transfer will enable better transfection rates and improve therapeutic outcomes.”

As alluded to earlier, all of the currently available CAR-T cell therapies are autologous or personalized; however, allogeneic CGTs are already approved. “The first allogeneic CGT (Ebvallo by Atara Therapeutics) was approved by the EMA [European Medicines Agency] in December 2022,” he said: Research is ongoing into allogeneic or ‘off-the-shelf’ CAR-T cell therapies, which would improve accessibility of these therapies to patients. “In the CAR-T space, there are currently no allogeneic therapies available on the market. About 130 allogeneic CAR-T therapies are currently under development,” Siciliano adds. Of these therapies in development, the majority are still only in preclinical stages with only about 15 in Phase II clinical trials.

“While we are seeing some positive results in the allogeneic space, there are still considerable challenges in the development of allogeneic (off-the-shelf) [CAR-T cell therapies], in particular with regards to their immunogenicity, the risk of GvHD [graft versus host disease] and host immune rejection,” he confirms. “It will still take a few years before allogeneic CAR-T therapies will be available on the market. It is also safe to assume that once allogeneic CAR-T therapies do reach the market, they are likely to co-exist with autologous CAR-T therapies for the foreseeable future.”