For the field of cell therapy, the future is promising. With chimeric antigen receptor T-cell (CAR-T) therapies steadily advancing, there are now numerous FDA approved therapies for patients with blood-borne cancers, including B-cell non-Hodgkin’s lymphoma, acute lymphoblastic leukemia (ALL), and multiple myeloma (MM). In fact, the FDA recently approved Abecma (idecabtagene vicleucel), the first cell therapy approved by the FDA for heavily pre-treated adult patients with multiple myeloma.

However, in the face of these advancements, there are still challenges to overcome, including the length of time required to manufacture cell therapies, high costs, and logistical challenges.

Other primary complications may include:

• Toxicity: Two of the biggest safety challenges observed in oncology cell therapies include cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS). High-grade CRS, an acute inflammatory response characterized by fever and multiple organ failure is rare but can occur. Research is aimed at identifying factors that predict toxicity such as high tumor burden and identify ways to reduce toxicities without losing efficacy.
• Resistance and remission rates: Although up to 90% of patients with relapsed and refractory ALL experience a complete response to CAR-T cell therapy, a subset of these patients will relapse. Mechanisms of resistance can include antigen loss, immunosuppressive tumor microenvironment, and decreased CAR-T cell persistence. Avenues of research to mitigate these mechanisms of resistance include exploration of bi-specific CAR-T cells that recognize multiple antigens, testing different subpopulations of T cells such as stem cell memory T cells, experimenting with the type and combination of co-stimulatory molecules, adjusting ex vivo culture conditions, or “armoring” T cells to express immune stimulatory cytokines.

Despite the current hurdles, the field is focused on applying cell therapies to solid tumors building off the compelling evidence and multiple approvals in hematologic malignancies. However, there are additional challenges that arise in solid tumors.

One of the largest hurdles is selecting a suitable antigen. In solid tumors there isn’t a universally expressed target like in hematologic malignancies. To avoid toxicity when CAR-T cells bind the target antigen expressed on normal tissues (on-target, off-tumor toxicity), researchers must identify antigens that are broadly expressed on tumor cells with limited to no expression in normal cells. It has been difficult to find such a target. By genetically engineering T cells to use logic functions (e.g., AND, OR, AND NOT) researchers are improving solid tumor targeting and are avoiding on-target, off-tumor toxicity. These novel solid tumor targeting approaches are starting to enter the clinic.

Trafficking CAR-T cells to the tumor site is an additional obstacle. Researchers are currently investigating the use of chemokine receptors to help direct the CAR-T cells to the tumor, though this is proving challenging as tumors secrete different types of chemokines. An alternative strategy being considered is finding ways to deliver CAR-T cells directly, or close, to the tumor as done in brain tumors and ovarian cancer.

Another issue to overcome in solid tumors is an immunosuppressive tumor microenvironment (TME). Scientists are using several strategies to modulate the TME, including cytokine expression, combination checkpoint blockade or genetically knocking out PD-1, and developing new approaches to limit T cell exhaustion including transient inhibition of CAR signaling.

Once a therapeutic is ready to head into clinical trials, there are yet more challenges to overcome. Cell therapy trials require access to ICU beds should high grade toxicity occur, sites that have expertise in cell therapies must be identified—there is a great deal of inter-departmental collaboration and logistical management that needs to occur for this process to be successful for patients.

The Solution: Finding the Right CRO

The list of novel approaches to improve cell therapy outcomes is rapidly growing and scientific advances in the lab are outpacing the translation of these advancements to the clinic. As advanced therapies are tested in clinical trials, it’s imperative that biotech sponsors have the support of a highly experienced CRO partner with oncology cell therapy clinical expertise and and understanding of how to test novel investigational agents safely and effectively in patients.  

One way researchers and sponsors can better arm themselves in this challenge is to work with a single CRO that can help them navigate the entire process.

A successful cell therapy clinical trial not only requires an understanding of the right sites; the sponsor must also partner with experienced teams who have the knowledge to complete regulatory submissions, training of site staff, and resourcing the trial for monitoring – while working through vast amounts of data. They must also have a robust and streamlined safety reporting process and understand the details around all of the critical logistical steps required to manufacture and treat patients with highly personalized and potentially toxic cellular therapies. Finally, flexible solutions for a patient-centric long-term follow-up phase is necessary for many genetically modified cell therapies.

Conclusion

There is no doubt that cell therapy specifically targeting solid tumors is one of the most exciting developments in the oncology space. The industry is finding new and innovative ways to tackle the associated challenges and it’s changing the way researchers, clinicians and patients think about cancer treatment.

At IQVIA Biotech, we recognize timelines are critical and every second counts. Our dedicated oncology teams have the experience to support the complex nature of oncology cell therapy trials from first-in-human to registration.


Contact us to discuss how we can help support your oncology cell therapy clinical trial.