Howard L. Kaufman, MD: We’ve already mentioned the central role of T cells, and so part of the thinking around adoptive T-cell therapy is that if the T cells are being suppressed in the patient with cancer, maybe you could take those T cells out of the patient and really reengineer them to be much stronger at either recognizing or mediating effective functions against cancer. And so there’s interestingly been a lot of approaches to this.

One possibility is you could actually go to the tumor site where the tumor reactive T cells might be. And even though they may not be as effective as you want them to be to clear a tumor, by taking them out of the body, separating them out, and then exposing them to other growth factors, such as interleukin-2, you could grow them up, make them stronger, and then give them back to the patient. And it turns out that that actually works pretty well, especially if you can pretreat the patient sometimes with non-myeloablative chemotherapy to get rid of the existing T cells. Some people have used radiation to do the same thing. And really, this has been a lot of the pioneering work in the surgery branch, which has shown a lot of success there.

Another strategy is to genetically engineer these T cells so that if they’re not recognizing the cancer, you could put in, potentially, a T-cell receptor that targets a known tumor antigen and use those. And more recently, there’s been work using what’s called chimeric antigen receptor T cells, or CAR T-cells for short. These are used in almost an antibody chain that can target an antigen, and then you can actually tack on to those various T-cell stimulatory domains, and then you can transfer those back into patients. That’s shown particular promise in CD19-expressing hematologic malignancies, where that work is actually far along.

Mark A. Socinski, MD: So, John—and, actually, I’d be interested in Howard’s opinion on this, too—is every cancer immunogenic?

John V. Heymach, MD, PhD: Yes. It’s a great question, and Howard brought up something that I think is a very important idea that people are thinking about, but it also points out the complexity. And it’s the following idea: that if you’ve got a lot of mutations, you should have a lot of new epitopes, and you should be more immunogenic. Well, we know some cancers that had very high mutation burdens, but are not particularly immunogenic. Small-cell lung cancer is one. Even though it’s very genomically unstable and the chromosomes are just a mess, the immune system doesn’t recognize it that well. So, it suggests that there are mechanisms that the tumor has to suppress the immune system, even when it does have a high mutation burden. Pancreatic cancer has a fair number of mutations; it doesn’t tend to be immunogenic. This illustrates that the number of potential epitopes isn’t the only predictor of whether something is going to be immunogenic. We have to start understanding all the different components of what suppresses the immune system and what can stimulate it.

The other thing is that things that are immunogenic are not always mutations. There’s a whole family of antigens out there. We call these the testes antigens; so MAGE-A3B, an example, and MAGE-A10. And they’re not mutated, but they’re typically suppressed during the normal adult development, where they may come on during certain parts. So, the immune system still recognizes them as foreign. And so these are some of the new approaches that are being taken. Can we use that as something to stimulate the immune response? Because tumors often express these.

Howard L. Kaufman, MD: I agree. I think there are different ways to get to immunogenicity, whatever that is. So, if you don’t have a good antigen, we now know that there may be other factors, such as local radiation. We’ve been hearing about this abscopal effect where you radiate a tumor, and you can see regression elsewhere. We think that’s because you’re generating potentially new antigens at the site of the radiation, which can then stimulate immune response. The other interesting story that’s emerging is that, in addition to this mutation burden, some cancers that are mediated by a virus—for example, HPV tumors—the y-tumors are immunogenic.

John V. Heymach, MD, PhD: Yes. That’s an interesting thought, because if you’ve got an antigen that the tumor doesn’t depend on and it isn’t obligatory, well, you may mount an immune response, but the antigen may just get turned off and that’s how you could escape. But if you’ve got, for example, an HPV-positive head and neck or cervical cancer, every cancer cell’s got HPV, and I haven’t ever heard a mechanism described to get rid of the virus there.

Mark A. Socinski, MD: Well, fascinating stuff.

Transcript Edited for Clarity