With the explosion of immunotherapy in oncology, the checkpoint inhibitors (Pembrolizumab, Nivolumab, Ipililumab, etc.) are being used in virtually every type of cancer. Now we are seeing the increased application of chemotherapy drugs combined with one or more immune agents to further improve outcomes.
Work conducted by James Allison, PhD and Tasuku Honjo, MD, PhD for which they received the Nobel Prize 2018, led to a new understanding of human immunity.
They found that these treatments worked by removing the immune system’s blockade.
Based upon these groundbreaking observations, antibodies that could “unblock” the immune system’s “log jam” leapt to the head of the class. Where immunologists for decades had tried to “step on the immune system’s gas pedal”, the new approach found it better to release the “emergency brake” and allow the immune system to roll into action.
Over the years, it became evident that not every tumor was "hot", meaning that the immune system could not recognize the tumor’s presence so the immune cells that were supposed to go after the cancer remained asleep at the wheel. To enhance immune recognition of cancers a variety of approaches have been adopted.
One approach uses a combination of immune drugs to first increase immune cell infiltration and then cause immune cell activation. A second approach uses radiation or chemotherapy to cause cancer cell injury leading to the release tumor proteins (antigens) that enhance immune recognition, all intended to wake up the “sleeping” immune system.
In advanced lung cancer, Dr. Corey Langer at the University of Pennsylvania was one of the first to combine chemotherapy with an immune checkpoint inhibitor and nearly doubled the clinical response rate (55% vs 29%) (Langer, C et al Lancet 2016). A more recent study (Checkmate 9LA) showed when two chemotherapy drugs were combined with two immune drugs survivals were even further improved.
It has since been shown in an aggressive form of breast cancer (triple negative) that the addition of immune therapy to a chemotherapy drug improves progression free survival (Schmid, P. NEJM, 2018). These results got even better when two chemotherapy drugs were combined with immunotherapy as 64.8% of patients showed complete resolution of all tumor at the time of surgery (pathologic complete response) (Schmid, P NEJM, 2020).
With all of this interesting data, the question is: What is the best chemotherapy to combine with immune therapy in breast, lung or for that matter any cancer?
With the use of chemo-immunotherapy, there is a delicate balance between too much chemotherapy and too little. Too much runs the risk of damaging the very immune system response that you are depending upon to do the job. Too little chemotherapy (or the wrong drug) and you run the risk of not damaging the cancer cells enough to get the release of tumor proteins to give the immune system the “wake up” that you so desperately seek. It would seem that the selection of the best chemotherapy drug combined with immune therapy has the best chance of achieving durable benefit.
We know that carboplatin is active in triple negative breast cancer and that carboplatin plus Taxol may be better but there are a lot of drugs that are active in triple negative breast cancer (Docetaxel, Capecitabine, Vinorelbine, Cytoxan, PARP inhibitors, etc.) and we haven’t even begun to talk about drug combinations like Cisplatin plus gemcitabine that we developed (Nagourney, R et al., J Clin Oncol, 2000) that is likely better still.
Similarly, in lung cancer do we know that one doublet like carboplatin plus Pemetrexed is better than the others (carboplatin plus Taxol, carboplatin plus vinorelbine, carboplatin plus gemcitabine, etc.), all of which have established track records in this disease?
A striking example arose when a 66-year-old gentleman arrived in my office in March of 2018 with extremely advanced lung cancer. It had completely overtaken and collapsed his right lung, invaded into the mediastinum (central tissue structure of the chest) but fortunately had not yet spread to other organs. As I scanned over the CT scans that he provided for my consultation, I was absolutely amazed that he was sitting in front of me.
In his case the drug doublet of carboplatin plus Taxol was combined with immunotherapy to which we then added radiation. He tolerated the treatment well and now fully two years following his original diagnosis remains in complete remission. He is one of the most remarkable examples of combined modality therapy that I have ever witnessed.
Future gains in this field will likely come once we can optimize the cancer-cell-killing effects of our drugs and radiation with the most effective immune therapy.
Our laboratory is actively studying patients with advanced lung, breast, and other cancers, who are themselves candidates for immune combinations to identify the best drug (s) to achieve the “priming” effect for subsequent immune treatment.
I am often troubled by the slow pace of progress in medical oncology but am encouraged by some these new findings in triple negative breast, advanced lung and other cancers and am enthusiastic about the prospect of combining rational drug selection with immune therapies as we see improvements in these previously uniformly lethal malignancies.
As always, I appreciate your thoughts and comments.
Dr. Robert Nagourney, has been internationally recognized as a pioneer in cancer research and personalized cancer treatment for over 20 years. He is a TEDx speaker, author of the book Outliving Cancer, a practicing oncologist and triple board certified in Internal Medicine, Medical Oncology and Hematology helping cancer patients from around the world at his Nagourney Cancer Institute in Long Beach, California. For more info go to NagourneyCancerInstitute.com