The Expanding Role of CAR T Cells in Lymphoma and Leukemia - Episode 13
David Miklos, MD:In this analysis of the sponsored Allogene [Therapeutics] work, which has an interesting history, these were the founders of Kite who then moved on to a new project. Today, we’re seeing the first published presented observation in lymphoma that we might be able to take out of the can and have super donor cells, allogeneic and prepared to become stealthlike. The stealthlike notion of this is deep lymphodepletion of the recipient in the setting of making the CAR [chimeric antigen receptor] itself resistant to the lymphodepletion by removing CD52 with technologies. Avoiding the cell against the recipient risk of graft vs host disease by removing the α chain of the TCR [T-cell receptor]. Both of these deficiencies are only limited by the current level of technology, which is not better than about 85%.
What is interesting is that the 2 genetic modifications are occurring in the same cells. The cell that gets TCR knocked out is the same cell that has the CD52 removed, and therefore now is resistant to an antibody against CD52 and lymphodepletion.
Stephen J. Schuster, MD: If there are some cells that didn’t successfully have 52 knocked out, they get knocked out by the lymphodepleting alemtuzumab-like antibody that’s used in part of the protocol.
David Miklos, MD:That’s exactly what I’m saying.
Stephen J. Schuster, MD: You’re right, you get a mixture. When you make these cells, you get a mixture of cells that have knockout of CD52, cells that have knockout of TCR-α, and cells that have knockout of both. Most of them, of these 3 variants, are going to have a CAR receptor. This is a multiplex genetic engineering event, which the 2 of us with gray hair get excited about.
David Miklos, MD: We’re very excited.
Stephen J. Schuster, MD: I want to know what the younger people think, particularly Loretta.
Loretta J. Nastoupil, MD: The most striking thing is when we identified a patient and treated within 2 weeks, which I think really gets to the point of you’ve got 1 shot at this. Time matters. Get it in quickly. One of the potential caveats to this specific agent, though, is they had rituximab built in as a safety, which was part of their earlier development. And you had to have patients who didn’t have recent rituximab, or at least not much circulating rituximab. This did limit some of the application, but that’s going to go away in the next iteration.
Caron A. Jacobson, MD: What do people feel about lymphodepletion with the CD52 antibody? David mentioned it’s deep lymphodepletion.
Stephen J. Schuster, MD:…Risky business.
Matthew J. Frigault, MD: With the toxicity profiles, you would predict a lot more viral reactivation. There were some CMV [cytomegalovirus] and reactivation reported. With the advent of letermovir, that could mitigate some of the issues that we’re seeing. But it’s like bendamustine. It does have implications for long-term, deep lymphodepletion, although it took a couple of months before you saw ALC [absolute lymphocyte count] recovery. That would be sufficient for harvesting for an autologous product in that case.
David Miklos, MD: Full disclosure: I’m an investigator, right? I’ve seen some of this. I will only speak to the 23 patients who are presented at American Society of Clinical Oncology today. There is no neurotoxicity so far, zero, zip, nada, nothing. There’s no GVHD, none. There’s massive expansion of these CAR T cells in the patient with, again, greater than 60% overall response rates, greater than 50% complete response. And they’re showing some durable responses in the total cohort that are CR [complete response] greater than 37% out of the can with low doses. If you go to the higher dose, infusion is 360 million per recipient. The 3 dose cohorts were 40, 120, and 360. The 360, those numbers are greater than 50% CR rates, which is something. Matt, what you’re saying is that if you knock out other cells besides T cells using a CD52, you may be removing a lot of the neurotoxicity triggers, and the monocyte and myeloid cells may be getting profound depletion in addition to the T cells.
Stephen J. Schuster, MD: Would you expect that you’re not going to see much IL6 at all, because you’re killing all your macrophages with the anti-CD52. That’s a good agent to treat patients with refractory CRS [cytokine release syndrome] with.
David Miklos, MD: We all said it.
Stephen J. Schuster, MD: Everybody said you have to pay a price for that.
David Miklos, MD: Pay the piper.
Stephen J. Schuster, MD: Lymphodepletion, and that’s infection and potential viral reactivation. And you’re mentioning strategies to get around it.
Transcript Edited for Clarity