Case Presentation or Single-Patient Trial?

David J. Kerr, CBE, MD, DSc, FRCP, FMedSci


March 13, 2017

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Hello. I am David Kerr, professor of cancer medicine at the University of Oxford. As we approach and embrace this period of precision medicine, I wonder if we are getting closer to the single-patient trial. I spent a whole career in which we have done large trials of thousands of patients. We have recruited tens of thousands of patients to an adjuvant colorectal trials portfolio over the past 20 years or so.

There is a really interesting observation in the New England Journal of Medicine from Steven Rosenberg's lab.[1] Steven Rosenberg, as we know, is one of the founding fathers of modern tumor immunology. The article gives insight into how we can almost literally do a trial in a single patient.

A few years ago we showed that pulmonary metastases from patients with colorectal cancer are relatively enriched with KRAS mutations.[2] In the primary tumor and in hepatic metastases, instances of KRAS mutations are about the same: 30%-40%. But in pulmonary metastases the instance of KRAS mutations is higher, at 60%-65%.

Rosenberg and his team found a patient with pulmonary metastatic colorectal cancer in one of their NIH trials. They resected two or three of the cancer nodules and used this material to isolate, purify, and clonally expand tumor-infiltrating lymphocytes. Using some very clever technology, they expanded the clones that recognized mutant KRAS.

This has been a vaccine target for drug companies for decades, and no effective mutant RAS drugs have appeared yet. They grew the CD8+ cytotoxic T lymphocytes ex vivo and infused them back into the patient after some conditioning treatment of cyclophosphamide. They infused about 1.1 x 1011 lymphocytes. Quite a cell biological tour de force. They then followed up with some additional interleukin-2 treatment and got a very good response. Of the remaining seven pulmonary metastases, all had partial regressions. About 9 months later, one of the metastases started to regrow. They resected this and did some very nice molecular analysis, which showed that in the tumor clone that had escaped from control of these specific lymphocytes, there had been loss of the haplotype around chromosome 6. This is the area around which the HLA-antigen-presenting mechanism is found. Perhaps not surprising, the metastases of this particular subclone had immuno-edited itself—it had deleted the mechanism whereby mutant KRAS could be presented to the body's immune system.

Quite interesting. Is it a case presentation or is it a trial within a single patient? What it tells us is that for truly sustainable responses that head toward a cure in immunotherapy, our dependence on ablation of a single antigen—even if it is associated with a driver oncogenic mutation—may not be enough. We may need to have a multivalent or pluripotent approach. That does not come as a surprise to us cancer doctors and biologists. A lovely story. I truly think that it could be considered a clinical trial within a single patient.

I would be really interested in what you think, as always. I would be very interested to see any remarks or posts that you might care to make on this video. Thank you for listening.


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