Cancer research is experiencing a paradigm shift with the introduction of innovative therapies like messenger RNA (mRNA)-based treatments and chimeric antigen receptor T-cell (CAR T) therapy. The development and use of immunotherapy and precision medicine have sparked global interest due to their potential to harness the body's immune system to fight cancer more effectively. Both therapies have demonstrated promising outcomes in clinical trials, particularly in refractory cancers. “Advances in targeted cancer therapies are integral to improving overall remission rates and reducing damage to healthy tissues,” explains Dr. Beatrice Setnik, PhD, Chief Scientific Officer at Altasciences.

Crucial nonclinical data gathered from mRNA and CAR T-studies

Nonclinical studies in mRNA and CAR T-cell therapy are essential for evaluating the efficacy and safety of these cutting-edge therapies before they reach first-in-human clinical trials. Assessing endpoints such as potential toxicities, dose-limiting effects, immune responses, on-tumor and off-target activities, biodistribution and persistence, and the presence and severity of cytokine release syndrome (CRS) ensures that the therapies target cancer cells effectively without harming healthy tissues. “With a comprehensive understanding of the therapeutic mechanisms and risks, sponsors can prioritize resources for their most viable compound, as well as determine safe dosages and therapeutic windows for their clinical trial design,” explains Dr. Norbert Makori, Vice President of Toxicology at Altasciences.

Clinical research on CAR T-cell therapy: Changing the dynamic of cancer treatment

In CAR T-cell therapy, a patient’s T cells are engineered to express a synthetic receptor (the CAR) that targets specific antigens on cancer cells. The FDA has approved this type of immunotherapy for certain hematologic cancers, and ongoing clinical trials are exploring its application in other malignancies.

Several CAR T-cell therapies, such as tisagenlecleucel and axicabtagene ciloleucel, have been FDA-approved for B-cell malignancies like acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma. Clinical trials in these cancers have reported long-term remission in patients who had been non-responsive to other treatments. Current developments include:

1. Ongoing Clinical Trials in Solid Tumors: Solid tumors often present a hostile microenvironment that suppresses immune responses and can cause CAR T-cells to malfunction or become exhausted. They also present physical barriers that make it difficult for CAR T-cells to reach the tumor site. Nevertheless, clinical trials are underway to evaluate the use of CAR T-cells for treating solid tumor cancers, where researchers are focused on identifying suitable targets for CAR T-cell therapy, such as HER2 in breast cancer and EGFR in lung cancer.
2. Next-Generation CAR T-Cells: Clinical research is advancing towards creating next-generation CAR T-cells with enhanced functionality. One field of inquiry is the development of CAR T-cells that target more than one antigen (dual-targeting CARs) or have “switch receptors” that act against repressing signals from the tumor microenvironment. Another area is the design of allogeneic (off-the-shelf) CAR T-cells, which would allow for the treatment of multiple patients with a single product, without the need for individualized cell engineering.
3. Toxicity and Safety Concerns: Clinical trials have identified two major safety concerns—CRS and neurotoxicity. CRS results from an exaggerated immune response, where cytokines are released in large quantities. Severe cases can cause inflammation, rash, low blood pressure, high fever and organ damage. Neurotoxicity can lead to confusion, seizures, or coma in severe cases. Researchers are exploring methods of mitigating these side effects, such as administering drugs like tocilizumab (an IL-6 receptor blocker) or steroids during treatment.

Clinical development of mRNA-based cancer therapies

mRNA-based cancer therapies involve delivering synthetic mRNA into cells to instruct them to produce proteins that trigger an immune response. Clinical research in this area is focused on developing mRNA cancer vaccines and immune modulators that enhance the body's natural tumor-defense capabilities.

1. mRNA Cancer Vaccines: Early clinical trials have mainly focused on testing mRNA vaccines against various cancers, including melanoma, lung cancer and colorectal cancer. For example, BioNTech initiated clinical trials with its mRNA-based cancer vaccine BNT111 for advanced melanoma. These trials have demonstrated that mRNA vaccines can stimulate robust immune responses by activating cytotoxic T cells specific to tumor-associated antigens. 
   Moderna is investigating mRNA-4157, a personalized cancer vaccine, which is being administered in combination with immune checkpoint inhibitors such as pembrolizumab, for the treatment of solid tumors. Preliminary results from Phase I trials showed favorable safety profiles and signs of antitumor activity in certain patient groups.
2. Combination Therapies: Research into how mRNA vaccines work in combination with other therapies, like checkpoint inhibitors or CAR T-cell therapy, is in the early phases of clinical testing. The rationale is that mRNA vaccines can induce a strong initial immune response, while checkpoint inhibitors or CAR T-cells can enhance and sustain the attack on the tumor.
3. Challenges in Clinical Trials: Delivery of mRNA into cells, particularly in solid tumors, is a significant hurdle; lipid nanoparticle (LNP) delivery systems are being optimized to improve the stability of mRNA and ensure targeted delivery to the desired cells. Managing the immune response to avoid excessive inflammation or autoimmune reactions is another area where researchers are testing chemical modifications to mRNA molecules to reduce these side effects.

Future directions

As understanding of personalized and targeted medicine grows, we can except personalized cancer vaccines, sometimes used in combination with other therapies. CAR T-cell therapy will likely expand to target solid tumors, improving precision and reducing side effects in cancer treatment. This research is at the forefront of medical discovery, carrying with it the hope of delivering lasting benefits for people worldwide.