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ONCAlert | Upfront Therapy for mRCC

The Hype and the Hope of Immuno-Oncology Agents

Adi Diab, MD
Published Online:12:28 PM, Wed July 11, 2018

Adi Diab, MD: I want to talk about the immunotherapy progress over the past 10 years. We definitely beat the skepticism about the efficacy of immunotherapy, and that was a measure held, and many people would not believe this because they haven’t seen the translation of the science into clinical practice. And in the past 8 years, we have seen that translation. And as is expected in the field of oncology, with a new treatment, there are sometimes great hopes and sometimes unrealistic hopes that accelerate more than the science accelerates and that advance to understand how to overcome the resistance for the current immunotherapeutic regimens. So, there is definitely hope and there’s definitely expectations.

Our fear is that we may enter quickly a phase of premature disappointment from immunotherapy, and that should not be the case because we need to understand better the immunotherapy and understand the mechanism of resistance. This is not one answer for all patients. This has to be tailored. Sometimes it has to be tailored for one patient, because inside that patient different lesions of different tumors behave differently. And science has to be advanced. We have to obtain biopsies to understand that. So, the hype and the hope are there, and we just may need to maintain that balance as we advance and improve immunotherapy.

The high-dose IL-2 toxicity depends on largely 2 mechanisms. One, the rapid and the overactive immune stimulation of the immune system because the IL-2 immediately activate those 2 cells. And once you have these rapid proliferations, you have chemical reactions that lead to vasodilation and hypotension, and that’s associated with less perfusion of blood into the organs. So, that sometimes lead to organ dysfunctions in the kidneys, the heart, and the liver.

Another part of the toxicity is related to the alpha subunit of the IL-2 receptor, which is also expressed on endothelial cells, in particular in the pulmonary and in the lung endothelial cells. And when it gets activated by the IL-2, it leads to leaky vascular syndrome, which is associated with pulmonary edema, and that has become a big hurdle and limits the patient selection to who can be treated in the IL-2.

NKTR-214 is a PEGylated cytokine that eventually harnesses the IL-2 signaling pathway and provides a safety profile. One, by being PEGylated and the slow release of the PEGylation, which is pH dependent, it prevents or avoids the rapid stimulation of the immune system. So, the stimulation of the immune system is there, it’s sustained, but it does not peak very quickly and goes down very quickly. And that mitigates some of the immune toxicities that we see with the high-dose IL-2.

Furthermore, the idea that the PEGylation structure is located to block or to bias against binding into the alpha subunit of the IL-2 receptor, that also lead to avoiding of the pulmonary edema. And that’s in terms of safety. That drug was designed to be more safe and has a better therapeutic window than the high-dose IL-2. It allows it to be tested as an outpatient regimen, and that’s what the monotherapy trial with NKTR-214 established.

In terms of efficacy, the same thing, the biased signaling through the beta and the gamma subunits of the IL-2 receptor allow for expansion of effector T cells, as well as NK cells and the tumor microenvironment, but does not allow for the expansions of the T-regulatory cells that depend on the signaling through the alpha subunit when it’s merged with a beta and a gamma.

And that’s why there is a preferential expansion of the good anticancer cells versus our regulatory cells, that we don’t need them to be active while we’re having cancer. So, that’s the structure of the drug that gives it a superiority in terms of safety, and theoretically, we have a better immune-stimulation bias toward effector cells and less toward inhibitory cells.

Transcript edited for clarity.

Adi Diab, MD: I want to talk about the immunotherapy progress over the past 10 years. We definitely beat the skepticism about the efficacy of immunotherapy, and that was a measure held, and many people would not believe this because they haven’t seen the translation of the science into clinical practice. And in the past 8 years, we have seen that translation. And as is expected in the field of oncology, with a new treatment, there are sometimes great hopes and sometimes unrealistic hopes that accelerate more than the science accelerates and that advance to understand how to overcome the resistance for the current immunotherapeutic regimens. So, there is definitely hope and there’s definitely expectations.

Our fear is that we may enter quickly a phase of premature disappointment from immunotherapy, and that should not be the case because we need to understand better the immunotherapy and understand the mechanism of resistance. This is not one answer for all patients. This has to be tailored. Sometimes it has to be tailored for one patient, because inside that patient different lesions of different tumors behave differently. And science has to be advanced. We have to obtain biopsies to understand that. So, the hype and the hope are there, and we just may need to maintain that balance as we advance and improve immunotherapy.

The high-dose IL-2 toxicity depends on largely 2 mechanisms. One, the rapid and the overactive immune stimulation of the immune system because the IL-2 immediately activate those 2 cells. And once you have these rapid proliferations, you have chemical reactions that lead to vasodilation and hypotension, and that’s associated with less perfusion of blood into the organs. So, that sometimes lead to organ dysfunctions in the kidneys, the heart, and the liver.

Another part of the toxicity is related to the alpha subunit of the IL-2 receptor, which is also expressed on endothelial cells, in particular in the pulmonary and in the lung endothelial cells. And when it gets activated by the IL-2, it leads to leaky vascular syndrome, which is associated with pulmonary edema, and that has become a big hurdle and limits the patient selection to who can be treated in the IL-2.

NKTR-214 is a PEGylated cytokine that eventually harnesses the IL-2 signaling pathway and provides a safety profile. One, by being PEGylated and the slow release of the PEGylation, which is pH dependent, it prevents or avoids the rapid stimulation of the immune system. So, the stimulation of the immune system is there, it’s sustained, but it does not peak very quickly and goes down very quickly. And that mitigates some of the immune toxicities that we see with the high-dose IL-2.

Furthermore, the idea that the PEGylation structure is located to block or to bias against binding into the alpha subunit of the IL-2 receptor, that also lead to avoiding of the pulmonary edema. And that’s in terms of safety. That drug was designed to be more safe and has a better therapeutic window than the high-dose IL-2. It allows it to be tested as an outpatient regimen, and that’s what the monotherapy trial with NKTR-214 established.

In terms of efficacy, the same thing, the biased signaling through the beta and the gamma subunits of the IL-2 receptor allow for expansion of effector T cells, as well as NK cells and the tumor microenvironment, but does not allow for the expansions of the T-regulatory cells that depend on the signaling through the alpha subunit when it’s merged with a beta and a gamma.

And that’s why there is a preferential expansion of the good anticancer cells versus our regulatory cells, that we don’t need them to be active while we’re having cancer. So, that’s the structure of the drug that gives it a superiority in terms of safety, and theoretically, we have a better immune-stimulation bias toward effector cells and less toward inhibitory cells.

Transcript edited for clarity.
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