My work mainly focuses on finding therapeutic targets for small cell lung cancer. Small cell lung cancer is the most aggressive form of lung cancer; it is about 15% of lung cancer cases diagnosed in the United States, which is quite a bit of number, and it’s the most aggressive form. Most patients have aggressive disease at the time of diagnosis.
Another thing small cell lung cancer is very good at is hiding itself from the immune system. So most of the immunotherapy targets are the drugs that we have so far, they have very modest benefit when it comes to treatment of small cell lung cancer. My job and my work here that I’m presenting at AACR is to find that therapeutic combination that can enhance the efficacy of immunotherapy for small cell lung cancer.
What combinations are you working on?
The combinations that I’m mostly working on, so in our previous work we had found targets – DNA damage response, so the proteins that work in cell cycle regulation and DNA damage repair are vulnerabilities for this particular cancer type. So we found that if you target these proteins in small cell lung cancer you have a better chance of killing these cancers in vitro and in vivo, both in our cell lines and in our mouse models. Following that work which was published in Cancer Research and Clinical Cancer Research, there were several clinical trials that were for the DDR repair protein inhibitors.
We also found that there are other reports from other cancer types that if you have a higher DNA damage affiliation your immunotherapy works better if you have a DNA damage response vulnerability. So our hypothesis was that if you can combine a DNA damage repair inhibitor with immunotherapy you have a better chance of increasing the efficacy of the immune checkpoint blockade for small cell lung cancer. That was the hypothesis with which we began this project.
Has this combination been seen before?
This particular combination with DNA damage repair and immune checkpoint blockade, there have been reports in other cancer types but our study, which is now published in Cancer Discovery, was the first study showing that this works in small cell lung cancer, combining a PARP inhibitor or a CHK1 inhibitor, both of which are regulators of the cell cycle or DNA damage repair. If you combine that with a PD-1/PD-L1 blockade you completely regress tumours in mouse models. The good thing about this is we right now have FDA approvals of PD-1/PD-L1 blockade antibodies, both in the first line treatment, so atezolizumab has been combined now and is FDA approved for combination in the first line treatment and nivolumab is now approved for small cell lung cancer in the third line setting. We already have DNA damage repair inhibitors in the clinic so it would be very easy to combine these two, going to patients. We think that this would work very much; a preclinical study is very, very encouraging because we see that tumour regresses and it’s a very stable regression and there is also a change in the immune modulation. So the immune microenvironment changes when you combine a DNA damage repair inhibitor with immunotherapy.
The work that I’ll be presenting is also combining chemotherapy, so this is a low dose gemcitabine. The beauty of that is, as I said, atezolizumab, which is now in the first line setting, FDA approved in combination with carboplatin and etoposide which is the first line treatment, so this combination is already FDA approved. So the next step would be to see how you can increase the response of the already approved drug. So we think that combining it with the DNA damage repair inhibitor could be the next step.
How does the toxicity profile look?
Preclinically we haven’t seen too much of toxicity but it hasn’t been tested in the clinic so we would like to see how that pans out in the clinic. But preclinically we haven’t found too much toxicity because we are using a very low dose of each drug. They are so potent together that we don’t have to use a very high dose preclinically so the toxicity profile preclinically is very encouraging. But we have to see, still, how it pans out in the patients.
The field is really going forward; small cell lung cancer was a widely ignored disease, there was no treatment almost for the last 3-4 decades and work from our group and from others has really taken it forward. We now know a lot more about the disease, the profile, the biology and the therapeutics than we knew before. We think that with the FDA approvals in the last few months that we are going forward in the right direction and we have found a way to enhance the efficacy of immunotherapy for this particular cancer type which really needs it.