Q & A: Dr. Sidi Chen, KCA-CRI CLIP Grant Recipient

Sidi Chen, PhD, was named the 2025 Kidney Cancer Association-Cancer Research Institute Clinic and Laboratory Integration Program (CLIP) Investigator to research “Initial development of a CAR-T-drug conjugate against solid tumor and application in kidney cancer.” Dr. Chen, Associate Professor of Genetics and of Neurosurgery at the Yale School of Medicine, plans to pair chimeric antigen receptor (CAR)-T-cell therapy, which has been very successful in treating blood cancers but less successful in treating solid tumors like those in kidneys, with proven anti-kidney cancer drugs and test how effective the combination might be at treating kidney tumors in a laboratory setting. We spoke with Dr. Chen about his work and what it might mean for patients.

What is CAR-T cell therapy and why are solid tumors like kidney cancers less responsive to it?

CAR-T cell therapy is a type of immunotherapy where we take a patient’s own T cells, a type of white blood cell, and genetically modify them to recognize and attack cancer cells. It has been remarkably successful in treating certain blood cancers like leukemia and lymphoma. However, solid tumors like kidney cancer are much harder to treat with CAR-T therapy. This is because solid tumors create a tough and hostile environment that prevents T cells from getting in and working effectively. The cancer can also vary more in solid tumors, and that makes it harder for the therapy to hit its target consistently.

How have you manipulated the CAR-T cell mechanism to potentially overcome the challenges posed by solid tumors like kidney cancers?

We’ve developed a new type of therapy called CAR-T-drug conjugate, or CAR-T-D-C for short. Think of it as a “2-in-1” treatment: it combines the power of CAR-T cells with the punch of chemotherapy. Using a special chemical technique called “click chemistry,” we attach a chemotherapy drug to the surface of the CAR-T cells. This allows the CAR-T cells to bring the drug directly to the tumor site, where it’s released and helps kill cancer cells more effectively. We’re using approved drugs like Monomethyl auristatin E (MMAE), which is already in use in some cancer treatments, but delivering them in a much more targeted and safer way.

How is this new CAR-T cell therapy different from existing targeted therapies for kidney cancer?

Current targeted therapies, like antibody-drug conjugates (ADCs), rely on cancer cells to swallow the drug so it can work. But many kidney cancer targets, such as the protein CA9, don’t “swallow” well, so those therapies don’t work as effectively.

Our approach gets around this problem. CAR-T cells don’t need the cancer cells to internalize the drug, they bring it right to the tumor and help release it in the tumor environment, where it can do its job. This makes our therapy potentially effective even against cancers that are resistant to traditional methods.

What would be “successful” outcomes of this research project – what kinds of cellular behaviors are you looking for?

A successful outcome would be seeing our CAR-T-D-C therapy shrink or eliminate tumors in laboratory models, especially where traditional CAR-T or chemotherapy alone has not worked. We are looking for CAR-T cells that can reach the tumor, kill cancer cells more efficiently, and do so without harming healthy tissues. We’re also hoping to see signs that this treatment wakes up the body’s natural immune response, helping it fight the cancer more broadly, what we call “systemic immunity.”

When could we see how well CAR-T-D-C therapy works in people with kidney cancer?

We’re currently in the early stages – testing in cell cultures and animal models. The results are promising so far. If all goes well, we hope to move this toward translational studies within a few years, for evaluating the feasibility of future clinical trials in patients. Before we can do that, we’ll need to complete safety testing, refine the treatment, and work closely with clinical collaborators and regulatory agencies to ensure it’s potentially safe and feasible for human testing.

What excites you most about this research?

What excites me most is that we’re combining two powerful approaches, cell therapy and targeted drug delivery, into a single therapy that could finally make CAR-T effective against solid tumors like kidney cancer. This could open new doors for patients who currently have few options. The most important thing for patients to know is that we are working to create smarter, safer, and more effective treatments. We are aiming not just to slow cancer, but to eliminate it, and to do so in a way that is tailored, innovative, and patient-focused.

What does it mean to you that there are kidney cancer-specific grants available for investigators like you with this research interest?

It means a great deal. Kidney cancer is often overlooked in cancer research funding, yet it has a significant impact on patients and families. For example, the Department of Defense has just dropped it’s Kidney Cancer Research Program funding mechanism in 2025, which drastically impacts the kidney cancer research field.

Having a grant specifically focused on kidney cancer allows us to take risks, innovate, and push boundaries in ways that general funding might not support. It shows a commitment to advancing new therapies for a disease that urgently needs better treatment options, and we’re proud to be part of that mission.