Explore Developments in CAR T-Cell Therapy for CLL (Podcast)

CAR T-cell therapy brings the promise of improved outcomes for patients with chronic lymphocytic leukemia (CLL).

“What makes CAR T therapy different from standard of care therapy such as small molecules is that these cells that are engineered with a CAR will stably express the protein and also persist after tumor is cleared,” says Vice Chair of the Center for Immunotherapy & Precision Immuno-Oncology, J. Joseph Melenhorst, PhD. “In essence, it's a self-replicating drug that continuously suppresses tumor recurrence. Since the first two patients were infused with CAR T cells in the summer of 2010, we have observed that these patients with CLL who achieved remissions tend to sustain remission, and we claim that to be a cure. Findings of these two patients were published in Nature of 2022.”

In a recent episode of Cleveland Clinic’s Cancer Advances podcast, Dr. Melenhorst discussed:

• The CAR T-cell treatment landscape
• Challenges of treating CLL, including T cell exhaustion
• Innovations underway to improve CAR T-cell therapy efficacy
• Improving access and time to treatment of cell therapy

Click the podcast player above to listen to the episode now, or read on for a short edited excerpt. Check out more Cancer Advances episodes at clevelandclinic.org/podcasts/cancer-advances or wherever you get your podcasts.

Excerpt from the podcast:

Dale Shepard, MD, PhD: Are there things being done to increase those response rates [of CAR T-cell therapy?]

Joseph Melenhorst, PhD: Some of the efforts that we undertook at Penn was to treat patients with the small molecule ibrutinib that inhibits CLL function, induces cell death, which we found, actually, and published in 2016 in Blood, not only de-bulks the tumor, if you will, but also allows restoration of T-cell function over the course of six-month treatment.

Based on those findings, we started the phase one trial, enrolling patients who had been on ibrutinib for six months after. T cells were collected for manufacturing with the CD-19 targeting CAR, and then infused in these patients, who were sustained on ibrutinib for at least a year.

Dale Shepard, MD, PhD: What do you think is going to be the next trigger to better therapy? What do you think is going to be the next break?

Joseph Melenhorst, PhD: I think it's a combination of factors. One is what we learned from ibrutinib, that targeting the tumor before collecting T cells is really important. I've since conducted studies here at the clinic to look at other modes of therapy. The time to response with ibrutinib is roughly five months. That's a really long time for patients to actually have measurable tumor reduction.

What we've seen in another small molecule study led by my post-doc, Dr. Celine Gregoire, and others, with collaborators in Europe, we've seen that venetoclax actually has a much shorter time to response. Also, obinutuzumab, which is an antibody that targets CD-20, similarly has a much shorter time to response.

On the other end, in my studies at Penn that I mentioned, we also looked at peripheral blood T cells and apheresed cells that were used for manufacturing to see if we identified a signal that could predict response to therapy. Actually, we showed that between 70 and 80% of CRs can be predicted based on that analysis. What we found in those analyses is that the population of T cells that sustains response, memory cells, are really important. The early memory T cell pool is relevant.

Going back to the challenge in CLL where a minority of peripheral blood cells are T cells, and a minority of that is even the early memory T cells, in non-responding subjects, even smaller, so we haven't been able to translate those findings into next generation therapies.

With the LLS-based trial with obinutuzumab, we see that within a matter of weeks we get a profound depletion of the CLL, recovery of T cell proportions. The numbers in T cells are always normal, if not higher, in CLL than normal, so this gives us the window of opportunity to collect the cells and then also to go after these early memory T cells. That's an innovation that's going to be part of my first phase one trial here at the clinic.

When we are thinking about CLL, how can we do better? First, we need to de-bulk. Second, we need to isolate these early memory T cells, and then third, we need to engineer them with CAR T cells and infuse them back into the patient. That's sort of the trajectory, what I'm thinking about in CLL.