Adoptive Cell Therapy in the Treatment of Melanoma

Key Takeaways:

• Patients with metastatic melanoma that has failed active therapies, who generally have fewer treatment options, may have improved survival with adoptive cell therapy or tumor-infiltrating lymphocytes (TILs).

• The initiator in the space was the Iovance study, in which patients were treated with lymphoid-depleting fludarabine/Cytoxan, TILs, and high-dose interleukin-2.

• Response was progression-free survival (PFS) of 18 months, followed by a confirmatory study with PFS of 10-12 months; the therapy is expected to undergo US Food and Drug Administration review this year.

• A current randomized, control trial of several European centers, including Netherlands Cancer Institute, has produced promising results with TIL treatment and has improved survival.

This transcript has been edited for clarity.

The topic for today is adoptive cell therapy, which, in melanoma, refers to tumor-infiltrating lymphocytes. There have been two important studies in the field of TIL, and the first one was the Iovance study, in which there was a phase 2 examination of patients who had failed essentially all other active therapies for metastatic disease. If they were BRAF-mutated, they failed BRAF/MEK. But most of them were BRAF wild-type and had all failed a PD-1 (programmed cell death-1) antibody. And something like >70% had also failed ipilimumab or a CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) antibody. And these are patients who ordinarily have no established therapy of any kind that will prolong survival.

In that study, initially, 66 patients were treated in a phase 2 study, and the rate of being able to grow the TIL was at least 90%.^[1] And a vast majority of patients received both lymphoid-depleting fludarabine and Cytoxan for a week, then got adoptive cell therapy with tumor-infiltrating lymphocytes that took 3 weeks on average to grow. And then, they got up to six doses of high-dose interleukin-2 (IL-2), and it was a one-shot treatment. You were done.

In that study, there was a 36% response rate called by the investigators, confirmed by centralized reading. And the median progression-free survival was more than 18 months, which is very impressive. And there was a significant rate of complete responders (CRs), which in the field of adoptive cell therapy is really the most important indicator of prolonged survival.

So, that was a very nice study. The results were attempted to be replicated in a further 69 patients. And in that study, again, a vast majority of patients had TILs successfully grown and treated with a week of fludarabine/Cytoxan. Then, they intravenously received their cells, and then, they got up to six doses of high-dose interleukin-2.

The response rate was a little lower. It was 30%-32%. The median progression-free survival was only 10-12 months. Not quite as good as in the original study, but there appeared to be a plateau of progression-free survival, some long-term responders, and some CRs, and again, in a patient cohort which had failed essentially all other effective therapies for metastatic disease.

So, that suggests that there's now a new therapy. That therapy will go up to the FDA (US Food and Drug Administration) sometime in the next 6 months. And if it is approved, I think we'll now have a new therapy for those who have failed all effective immunotherapies, and if BRAF mutated, had also failed BRAF/MEK.

Now, with the most recent ESMO (European Society for Medical Oncology) just a few weeks ago, the first randomized TIL trial was presented, which was carried out by a European group. That was carried out by a number of investigators in Europe. Chiefly among them was the Netherlands Cancer Institute, and John Haanen presented the data at ESMO.^[2]

It was a straight-up 1:1, essentially, randomized phase 3 trial; however, I think of it as a randomized phase 2 trial of 168 patients who were randomized after failing PD-1 antibodies to get either ipilimumab (a CTLA-4 antibody), or therapy with TIL in a virtually identical format as that used in the Iovance trial, where you got 7 days of fludarabine and Cytoxan. You got your TIL, which took 3-5 weeks to grow and expand outside the body, and then, you got up to six doses of high-dose IL-2.

It's a huge effort to do this sort of randomized study, but in this study, there's no question that there was a benefit in terms of progression-free survival. There was also a benefit in terms of overall survival, however, that didn't reach statistical significance.

And the hazard ratio for progression-free survival in that study was 0.5. That's a very impressive number for a relatively small study of 168 patients in a 1:1 randomization, and it says that your progression-free survival, preliminarily. Also, there's some evidence that there was a hazard ratio of about 0.8 for overall survival favoring TIL vs ipilimumab; we'll see with longer follow-up whether there's clearly a survival advantage.

Those are impressive numbers. And they suggest that the time has now come for TIL to enter the mainstream of melanoma therapy. That was a study done exclusively in Europe. I assume it's going to come to the EMA, the European Medicines Agency. And we'll see whether, both in the US and in Europe, if there's an approval for tumor-infiltrating lymphocyte adoptive cell therapy.

That's just the beginning. In the future, you're going to see less IL-2 use. You're going to see genetically modified TIL. You're going to see TIL grown in different ways to expand them to bigger numbers. You're going to see multi-administration of TIL, where you grow the TIL, and you give it on multiple occasions over time. Or you'll see drugs other than IL-2 given with the TIL, like PD-1 or ipilimumab/nivolumab. And I think there's a bright future ahead for adoptive cell therapy with TIL in melanoma.