Considerations for Use of TILs versus CAR T-cell Therapies

Transcript:

Amod Sarnaik, MD: Krishna, tell us a little about the safety and efficacy of TILs [tumor-infiltrating lymphocytes] in patients with advanced solid tumors based on the data presented in recent years?

Krishna Komanduri, MD: You highlighted it well. Obviously, there are some unique aspects of coordination. I’ve heard that the oldest CAR [chimeric antigen receptor] T-cell therapy patient was 92 years old, which is remarkably high. There are some modest, age-related limits. Age 75 is probably the reasonable upper limit. This looks a lot like our current landscape for autologous and allogeneic transplant therapies. There can be patients with comorbidities, and there can be patients who are older. Extremely old patients might be contraindicated. In the early trials of CAR T-cell therapy, the median age in the 3 pivotal trials of CD19 CAR therapies was under age 60. That age has been pushed forward as we understand how to do management and optimize characterization of early signs and problems and we get better at managing them. I’m confident that that will happen in the context of TIL therapy as well.

As you noted, 1 advantage of TIL therapy is that we don’t have to know about the target antigen. These are T cells that we already know in the context of a human immune response. They’ve gotten to the tumor and are around the tumor, so presumably they have learned to recognize the tumor and have already expanded, albeit in relatively modest numbers. These are interesting potential advantages.

In terms of toxicities, you highlighted them well. There’s the need for a moderate dose of cyclophosphamide. In some patients who are older or have significant impairment in performance status, that may be an issue. There’s the need to give IL-2 in a supportive care setting. This is not a therapy that would be administered in a community setting, at least not in the…foreseeable future, because of the need for hospitalization and specialized coordination—the collection of the tumor, cell therapy laboratories, and the clinical competency to infuse the cells, administer IL-2, and watch and support patients until they get out of trouble. Those are the key elements.

Amod Sarnaik, MD: Just to add a little on the toxicity piece, 1 of the inherent advantages of TIL-based therapy is that it’s a single infusion. After that, the patients don’t require additional treatment. Unlike other treatments that we’re more used to—including conventional treatments like immune checkpoint blockade—patients can accumulate cumulative toxicity as they get more doses of the agent. We see this a lot with chemotherapy, which doesn’t have the long-standing response rate.

With TIL, once you recover from the acute toxicity of the IL-2, and once the bone marrow recovers and the effects of lymphodepletion fade away, it’s relatively rare to get new-onset toxicity. I’ve seen a couple of cases of what has been termed on-target, off-tumor toxicity. That’s when the TIL tends to recognize an epitope on a normal cell that’s similar to what is seen on melanoma. Patients get vitiligo, which is loss of skin pigmentation. I had 1 patient with high-frequency hearing loss as well as some imbalance issues. The hair cells in the inner ear may share a target antigen that that particular melanoma had. There’s also some other chronic toxicity from the chemotherapy itself—neuropathy and the like. However, for the most part, patients recover and are able to return to their typical activities of daily living and have a similar performance status compared with before they started treatment.

Krishna Komanduri, MD: Great points, and a couple of things I think that are also worth highlighting is there are 2 major classes of toxicity that are relatively common with CAR-T cell therapy. Cytokine release syndrome [CRS] tends to usually in the first week or so after infusion of the CAR and then neurotoxicity syndrome or something that we call the immune effector cell associated neurotoxicity syndromes that typically happen towards the end of week 1 and week 2. These largely don’t happen with TIL therapy.

We do see some CRS-like blood pressure changes through the IL-2 but again CRS and ICANS [immune effector cell-associated neurotoxicity syndrome] which are well characterized and very common and almost canonical toxicities of CAR-T therapy we don’t see here. At least so far there are some other toxicities in CAR-T therapy that are emerging; delayed cytopenia, hemophagocytic syndromes, and other things that can be unique to some of the CARs that are administered. Largely I think we haven’t seen that.

There is again a little bit more excitement when the patients are receiving that IL-2 therapy, but once that goes away, which is quite quick—and again, the other important thing to know about IL-2 therapy is we don’t have to give a full course so if patients get toxicity, we can stop that. That does not necessarily obviate the responses that we see with TIL therapy, which means that really if the toxicities become excessive from the IL-2 we can just stop it and we certainly can see excellent responses even without giving a full course of IL-2 therapy.

Amod Sarnaik, MD: These are great points and just a final word on toxicity before we move on; I will say that in our institution we really have not had to use tocilizumab to manage the IL-2 toxicity for our TIL patients unlike what we see with CAR-T. One unique management issue may be a lot of our patients do have hypo pituitary disorders from their prior immune checkpoint inhibitor and the hypotension seen with the IL-2 especially sometimes makes it a little bit of a tightrope walk to decide whether to use some steroids or not, usually to combat potential exacerbation of adrenal insufficiency but aside from that I really haven’t had to use high dose steroid to mitigate other toxicity.

Krishna Komanduri, MD: That was my experience too. In a clinical trial setting, we’ll know more as these therapies move towards approval and we see labels that tell us the expected toxicity and the frequency of those toxicities, but your experience mirrors my own. I haven’t had to use tocilizumab and I haven’t seen a lot of steroids at all with these therapies.

Transcript edited for clarity.