NKTR-214 & Nivolumab: Synergistic Activity Across Tumor Types - Episode 9

Efficacy of NKTR-214 in the Tumor Microenvironment

July 11, 2018

Adi Diab, MD:When we increase the number of T cells in the tumor microenvironment, how do we achieve that? Do the existing T cells proliferate, or do we increase infiltration of the immune cells into the tumor microenvironment? Doing [T-cell receptor] sequencing using immunoSEQ technology, we found that we cause proliferation of the T cells in the tumor microenvironment. But that technology allowed us to identify new clones of T cells that were seen at week 3 after the treatment was initiated. Those clones had not existed at baseline. Does that mean that there has been trafficking to the tumor microenvironment secondary to the impact of the treatment of NKTR-214 and nivolumab (Opdivo)?

We looked back at the patients who received NKTR-214 alone in the EXCEL trial, which was a completely different patient population. We noticed the same effect: NKTR-214 alone can lead to trafficking of new clones of T cells that did not exist in the tumor microenvironment before treatment. However, after treatment they exist. This means that NKTR-214 leads not only to the proliferation of cells in the blood or tumor microenvironment but also to trafficking and infiltration of a new wave of T cells to the tumor microenvironment.

That has implications for what we call “showering the tumor microenvironment,” wave after wave with the new T cells. That can possibly reshape the tumor microenvironment, repolarize it, and lead to a tumor-killing repertoire of T cells. That’s the implication. That’s why it’s important. This leads to an increase in not only the number of existing T cells but also the number of T cells that newly invade the tumor microenvironment.

We initially spoke about the baseline demographics of patients in the study. In some of the patients who have high levels of LDH [lactate dehydrogenase] [or] liver metastasis or are PD-L1 [programmed death-ligand 1] negative, we’ve seen responses regardless of the status of these markers. But when we look specifically at those baseline immune features, such as the PD-L1 status or the number of CD8 cells at baseline before a treatment, you can see that for the patients who have high PD-L1—positive disease or, more importantly, have more than the median of CD8 at baseline, their response rate was 85% with a disease-control rate of 100%. That’s very impressive. But you can always say, “Well, make this richer.” Then you increase the responses in patients who are likely to respond anyway to that treatment.

So when you look at the patients who didn’t have high CD8 counts at baseline, you see that the response rate was 38% and the disease-control rate was 54%. That’s related to the feature that we just described. If you don’t have enough T cells in the tumor microenvironment, the ability of NKTR-214—in combination with nivolumab—…to increase them can increase the chance that the tumor microenvironment will respond to those invading T cells and make a tumor start to shrink, eventually killing the tumor.

Transcript edited for clarity.