Science

Collaborative Cancer Care: How CAR T-Cells and mRNA Vaccines Team Up

by
Trimero

Introduction: Unlocking the Potential of CAR-T Therapy in Solid Tumors

Chimeric antigen receptor (CAR) T cells have successfully treated relapsed/refractory B-cell neoplasms and multiple myeloma but have limited efficacy in solid cancers. The main challenges in solid tumors are the absence of highly-specific cancer cell-surface targets, leading to on-target/off-tumor toxicity and issues with T cell expansion and persistence due to antigen inaccessibility and the immunosuppressive tumor microenvironment.

Messenger RNA (mRNA) vaccines, known for their success against infectious diseases, are now being explored in cancer research. These vaccines utilize mRNA technology to stimulate the immune system against cancer cells. In cancer immunotherapy, mRNA vaccines offer a novel approach, holding promise for more effective and targeted treatments.

Targeting Claudin 6 for Solid Tumor Treatment

The phase 1 BNT211-01 trial explored the use of Claudin 6 (CLDN6)-specific chimeric antigen receptor (CAR) T cells, along with an amplifying RNA vaccine (CARVac), in treating relapsed or refractory solid tumors. CLDN6, a primitive tight junction protein, is a promising target for immunotherapy due to its high and specific expression in many solid tumors. Yet, suppressed expression in healthy adult tissues makes it an ideal immunotherapy target.

The trial focused on the safety and feasibility of this approach. Manageable toxicity was observed, with some patients experiencing cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome. The efficacy of the treatment was also notable, with an unconfirmed objective response rate (ORR) of 33% and a disease control rate of 67% in the evaluable patients. Notably, patients with germ cell tumors (GCT) treated at higher dose levels showed a higher response rate.

The study highlighted the potential of CLDN6 expression as a predictive biomarker, suggesting that higher levels of CLDN6 expression predict better treatment outcomes. This is significant as it could guide selection of patients most likely to benefit from CLDN6-targeted therapies.

This trial represents a significant step in using CAR-T therapies for solid tumors, a field where these therapies have historically faced challenges such as lack of specific cell-surface targets and poor expansion and persistence in the tumor microenvironment.

Defibrillating the brain: Advice for going to Oxford

by
Trimero

It’s been another year without much blogging, but we have a good excuse – we’ve been living in Switzerland for the past 18 months in a cozy village near Lake Zurich. As a result, our daughters are now fluent in German, and my wife and I have steadily improved our language skills.

After a two-year break, we’ve recently started traveling again, and it was great to see my team and friends. In September, I attended a symposium on cancer immunotherapy organized by my former boss, Ignacio Melero. Nacho gave a talk to celebrate 25 years of research on CD137. This T-lymphocyte co-stimulation protein has effectively eliminated tumors in animals but has not yet shown the same results in patients. Nacho discussed new strategies for improving the effectiveness of this type of antibody in both monotherapy and combination with other treatments. Nacho’s lab in Pamplona has been very productive, focusing on pre-clinical work, biomarker research, and pioneering clinical trials in the field of immunotherapy for liver carcinoma.

Defibrilating the brain. Life in the lab
Drawing by Maria Gonzalez Forero MD

I have fond memories of my time at the CIMA research center at the University of Navarra, where I learned much about tumor immunology and activating T cells to recognize and eliminate cancer cells. Every Wednesday, we had a “Journal Club,” where we would review and discuss relevant articles in our field. One of our pre-docs or post-docs would present the results of a recent publication. We would all carefully evaluate the paper, focusing on understanding the methods and how we can apply the findings. On some occasions, the techniques used were complex and new to us, so we would have to read the text multiple times and find additional sources to understand them fully.

I remember one Wednesday when we had a tough time understanding a paper, and none of us had asked any questions about the experimental model. That’s when Nacho, our dear boss, said something that has stuck with me for over a decade: “It’s time to defibrillate the brain.” 

This phrase means :

  1. To have a critical mindset,
  2. To understand how things work in-depth, 
  3. Ask questions when in doubt, 
  4. Strive for excellence. 

It was a valuable lesson for life in the lab and life in general.
This year, Dr. Melero is starting a new position at Oxford University. Good wind, good sea, and good science, Nacho!

Image generated by Dall-E 2