Pembrolizumab + Adoptive Cell Therapy Melanoma with T-Cell data. Tumor-infiltrating lymphocytes, and tumor-infiltrating lymphocytes recognize tumor antigens.
We looked at predictive biomarkers in patients who have received adoptive cell therapy. So just in brief adoptive cell therapy is a fairly complex treatment modality. That’s been administered to patients with melanoma and other tumor types.
The idea is that we resect a tumor. That harvest that harbors, both tumor cells and tumor-infiltrating lymphocytes, and that those tumor-infiltrating lymphocytes will actually recognize tumor antigens, but be somewhat exhausted. And that’s why the patient has had tumor growth. If we can expand those then in Vivo.
After resection of the tumor, stimulate them with various growth factors and then infuse them after some myeloablation to create immune space. If you will, then those tumor-infiltrating lymphocytes that are reinfused into the circulation will be expanded and will hopefully result in anti-tumor activity in other areas as well.
So, I develop this technology. They’ve been very successful in doing this and providing the cell therapy product, which can be administered at other sites, but they actually develop the product in their central facilities. So it’s the first of this kind of therapy for solid tumor patients. The particular study that we presented at ASCO involved, the biomarker work related to two melanoma cohorts.
One was a treatment-naive melanoma cohort that received the cell therapy plus pembrolizumab, and the other one was treatment experience. So in other words, patients whose tumors had previously been treated with PD-1 inhibitor-based therapies, and the purpose was to compare these two cohorts. So this was a nested comparison.
The ratios was 1 to 3 were, the cohort was much smaller in the treatment-naive patients. And it the big finding was the tumor mutation burden was not clearly associated with response to therapy. In fact, there was no correlation there which tells us that patients whose tumors have a low tumor mutation burden might also respond to cell-based therapy.
The other important finding here is that they compared the ality of the T cells. In the patient’s blood before and after the therapy. And it’s clear that after the therapy, there was expansion of the clones that originated in the tumor and those persisted for quite a while. So essentially there was a switch in the circulating T cells to produce a general population that was more likely to recognize the tumor.
Can this be used as a predicted biomarker?
And obviously the answer is no tumor because tumor mutation burden was not associated either in the treatment naive patients or the treatment experience, patients with response to therapy. So it was more of a learning tool than something that we can use for patient selection in the future.
The other question that I was asked was about the duration of response. Iovance has recently published new data where the duration of response was somewhat shorter than originally observed in the previous studies. The reason behind this was that the median drops when the patient in the middle develops recurrence.
So, it was driven by one or two patients rather than by the entire population. There still is. Tail at the end of the curve, which is just under 50% of patients remaining in response. Well over two years after treatment so there were a few, a number of queries about that. And overall the questions related to whether there was any particular phenotype of patients who was more likely to respond.
I think that the one thing that we have observed is that patients that were very heavily pretreated with immune checkpoint inhibitors were less likely to respond. Been patients who received a smaller number of cycles of Anti-PD-1. These studies were not part of the particular presentation at ASCO, but part of other studies that were done by the invest group and.
Not really. I think that it’s somewhat reassuring that patients who have low tumor mutation burden or tumor Neo antigen burden, that was the other measure that they looked at. So, patients with either low tumor mutation burden or low tumor, Neo antigen burden were equally likely to respond. So, I believe that it pro it.
It provides some reassurance, but clearly the numbers of patients enrolled in these trials was very small and a lot more validation will be required to make sure that this indeed is the case.
So, Iovance has expanded the studies beyond what was presented at ASCO. There’s also additional biomarker work. That’s being conducted to look for persistence of the specific clones, as well as the characteristics of those clonal. T-cells at a single cell level. Those studies are ongoing at present. And they’re very interesting from a scientific perspective.
The other future direction I believe is that Iovance is working on obtaining FDA approval to enable this product, to be available to patients at large of the, not in the setting of a clinical trial. And this will be done based on the phase two data.
Now, other than that, it’s an exciting treatment option. Clearly more data are needed to see how long the, these responses last we do have patients who have very durable responses. But the biggest question is the percentage of patients that develop these durable responses or cures, particularly patients previously been treated, other immunotherapies.
Harriet M. Kluger, MD, Professor of Medicine (Medical Oncology); Director, Yale SPORE in Skin Cancer, Yale Cancer Center; Director, Yale Immuno-Oncology Training Program; Harvey and Katherine Cushing Professor of Medicine and Dermatology, Internal Medicine; Associate Cancer Center Director, Education, Training and Faculty Development; Deputy Section Chief, Medical Oncology, at Yale School of Medicine. In this video, she speaks about the ASCO 2022 Abstract – Tumor mutational burden (TMB) in immune checkpoint inhibitor (ICI)-naïve and -experienced patients with metastatic melanoma treated with lifileucel, a tumor-infiltrating lymphocyte (TIL) cell therapy.
Summary:
LN-144 (Lifileucel)/LN-145/LN-145-S1 is an autologous TIL-based adoptive cell transfer therapy used to treat patients with unresectable or metastatic melanoma, advanced, recurring, or metastatic head and neck squamous cell carcinoma, and locally advanced or metastatic non-small cell lung cancer. The adoptive cell transfer therapy used in this trial involves patients receiving a nonmyeloablative (NMA) lymphodepletion regimen, followed by an infusion of autologous TIL and an IL-2 regimen. TIL plus checkpoint inhibitors will be given to patients in Cohorts 1A, 2A, 3A, and 3C. Autologous TIL will be administered as a single therapy to patients in Cohorts 1B, 1C, and 3B.