New approach generates more effective adoptive T-cell therapies faster, with fewer cells
Click Here to Manage Email Alerts
Adoptive cell therapies have proved highly effective for patients with certain advanced cancers, particularly melanoma and hematologic malignancies.
Nevertheless, the time it takes to manufacture these therapies means some patients will require additional bridging therapy or experience insurmountable disease progression. Finding a way to make cellular therapies faster and more accessible to patients is a driving force for Hannah Knochelmann, BS, a student in the MD/PhD program at Medical University of South Carolina.
Knochelmann is part of a group of researchers — including those from Medical University of South Carolina, Emory University and The Ohio State University — who reported on the production of adoptive T-cell therapies through a novel 4-day process that generates fewer cells faster but with potentially more potent cancer-killing capabilities.
Knochelmann spoke with Cell Therapy Next about the new process and how it could impact clinical care in the future.
Question: Can you explain your group's rationale for initiating this research?
Answer: Cell therapies have been very effective for patients, but they are extremely costly and it takes a long time to generate effective T cells. When I started graduate school, one of my main goals was to figure out a way to make this therapy more accessible to patients — to develop effective T cells in a faster manner.
One way to accomplish this goal is to cut down on cell expansion time, because it typically takes a couple weeks to grow enough active T cells in culture. Our idea was to circumvent this process by using a better cell type or a cell type that is more intrinsically therapeutic.
Our labs began to focus on a particular T-cell subset of CD4 cells — Th17 cells — and have done research with humanized and other preclinical models. Because these cells are more intrinsically therapeutic, we hypothesized that fewer would be needed, therefore reducing the amount of time needed to expand the cells. If we can accomplish this, then we can also reduce the cost of the therapy.
Q: What are Th17 cells and why did your research target these?
A: There are two main categories of T cells. First is CD8, including cytotoxic T cells, which is the more well-known subset. The second subset is CD4, which includes helper cells that support other immune cells.
Th17 cells are from the helper subset and produce the molecule interleukin (IL)-17. Their normal purpose within the body is to fight extracellular bacteria and fungi. Our approach is to redirect Th17 cells to tumors because of their functional qualities.
Q: Your research showed 4 days is the optimal duration to culture the cells, as shorter or longer times reduced the therapy's effectiveness. Why is this timeframe ideal?
A: A cell therapy comprises living cells that can change at any time. Early in the culture process the cells are still being activated, but after 4 days they ramp up their activation and can create effector molecules while expressing other receptors that provide support for their growth. At this point the cell's machinery is turned on, which allows it to respond to the environment and begin producing molecules that support its effectiveness against tumors.
Another aspect of this is that administration of our modified cells heightens the immune response in the recipient, with widespread activation of the immune system. The cytokine IL-6 was particularly important, and we found that these Th17 cells expanded only four days were able to elicit an IL-6 response in our animal models.
Q: For which adoptive cell therapies could this process be used?
A: We think it could have broad application for cellular therapy. Theoretically, we think it could be used for tumor-infiltrating lymphocytes by including the signals that these cells need in the culture dish. I also believe it can be feasibly used for CAR T cells.
Q: Are there plans to further evaluate this approach?
A: Our group has submitted applications for grants and is looking to start clinical trials to move these cells into the clinic.
It has been known for a number of years that Th17 cells are therapeutic. What we have shown thus far is that even during this very short culture time — during which there is a lower yield of cells — the cells are nevertheless more potent as a therapeutic.
There are barriers facing the field of cell therapy regarding the ability to isolate this subset of enriched T cells. Current practice trends toward providing as many cells as possible, but we believe the ability to enrich smaller numbers of more therapeutic cells is the direction the field will take. As manufacturing capability for these therapies expands, our approach will become even more feasible.
Q: What is the potential impact of this research on price, manufacturing time and access to treatment?
A: There is so much cost in the clinic that occurs upfront to deliver these therapies — including obtaining the patients’ cells, engineering those cells and then expanding them — and previous attempts to isolate Th17 cells would have added even more to the price. Coupling this shortened expansion process with an upfront selection process could be more fruitful, saving both time and money by avoiding a process that could typically take up to 2 months. If the proper cells are selected out, as our research has shown, then cell expansion can be shortened dramatically.
The field of cell therapy is moving toward obtaining these more therapeutic cells first and, as a result, will confound the notion that you need billions and billions of engineered cells to treat a patient. We can use far fewer cells, and I think that's a pretty big deal.
Our key takeaway is that less is sometimes more. We always thought that more T cells provided in a therapy would be better, but our work has found a situation where more T cells are not advantageous. This finding challenges the field to rethink its approach to cell therapy manufacturing. Hopefully, we will inspire more investigators to move forward with this shortened process and produce more effective therapeutic cells.
For more information:
Hannah Knochelmann can be reached at knochelm@musc.edu.
Collapse
Click Here to Manage Email Alerts