Cancer Gone Viral: Cell-engineering tackles cancers caused by HPV
TCR HPV Cancer therapy

Cancer Gone Viral: Cell-engineering tackles cancers caused by HPV

Dr. Talia Henkle
Dr. Talia Henkle

In 10 seconds? Researchers are tackling HPV-associated cancers with new, so-called ‘living’ cancer treatments. These engineered T-cell receptors make a patient’s immune cells target HPV proteins in tumors and suppress the cancer.

Hey, I thought the vaccine was successful in preventing HPV-associated cancers? Well, yes, but the vaccine is relatively new so many older people couldn't benefit from it and might have the misfortune of developing an HPV-associated cancer (like cervical, anal, and head and neck cancer). That's why researchers continue the search for better treatments for patients with these cancers.

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And how far have they gotten with it? OK, first a reminder. In our recent digest, we talked about how, if HPV is to cause cancer, it needs to unintentionally integrate its DNA into our genome and ramp up the production of its anti-death and pro-growth proteins named E6 and E7. ("Anti" and "pro" in this case are from the cancer's point of view). And while E6 and E7 may seem like our worst enemies, in this case, their integration into the tumor DNA is exactly what gives scientists hope for new therapies.

Why’s that? E6 and E7 are promising targets for cancer therapies because they are only present in tumor cells and absent from healthy tissues. So if treatments can be made to target those, they will kill cancer cells around the body with fewer unwanted side-effects (in theory)! And one of the ways scientists are targeting them is through a fascinating T-cell engineering approach–called T-cell receptor (TCR) engineering.

Yet another three-letter abbreviation..So are these like CAR-T cells? Pretty much. (Here’s a digest explaining CAR-T cells for reference) Except, instead of removing a patient's T cells and engineering them to have cancer-specific CAR receptors on their surface (essentially a very fancy cell surface antibody that will help the engineered cells target cancer and kill it), in this case, the cells are engineered to have HPV-specific TCRs on their surface. While the mechanics of target recognition are different, the concept is the same in that the majority of a patient’s (engineered) T cells will start to specifically target the cancer.

Sounds amazing, so everything is smooth and simple? Well, not exactly. Similar to CAR-T cells, patients in these studies got a blood draw to collect T cells and then received chemotherapy (which kills immune cells as well as cancer cells) to make ‘room’ for the newly engineered T cells, which otherwise wouldn’t be accepted by our bodies. Then they are infused with the TCR engineered cells. So, it wasn’t exactly a quick session for them.

OK, so I’m eager to hear how far this research has advanced! “Patience, my young Padawan learner!” I’m getting to it. Researchers first tried this approach by targeting HPV E6. In the first study of 12 patients with advanced-stage HPV-associated cancer that had failed to respond to multiple other treatments, 2 out of 12 patients saw long-lasting improvement in their cancer burden. Although the response was less than ideal, interestingly, the scientists were able to discern the reason for the treatment resistance seen by some of the patients. Using genetic sequencing, they saw that some of the tumors had developed particular mutations that made them resistant to T cell killing–prompting the authors to consider more in-depth genetic testing before administering treatment in the future.

Marked decrease in metastatic tumor burden (bright white spots) seen in a patient after treatment with E7 TCR-engineered T cells. Source: Nagarsheth NB, et al. Nature Medicine. 2021;27:419-425

2 out of 12… well, it seems like there’s room for improvement there. Right? But remember, these are patients who had the toughest to treat solid cancers, so 2 out of 12 is at least a start. Also, these therapies had significantly fewer nasty side effects than are typically seen with CAR-T treatments. (Although reading about all these clinical trials in advanced-stage cancer is what has made me so passionate about HPV vaccination and cancer prevention. I digress…) Next, the researchers tried this approach using TCR-engineered T cells against HPV E7. In this study, 6 out of 12 patients saw long-lasting improvement in their cancer burden. While these results seem like an improvement from the E6-targeting T cells, sample sizes are too small to say that with certainty.

So, what’s next? While responses aren’t perfect, they are suggestive that solid metastatic cancers can be tackled with engineered T cell therapies. Scientists are still hard at work trying to improve these treatments to overcome or avoid tumor resistance. The authors also proposed using these treatments at earlier stages in the disease to see if they might be more effective.

Can we make a vaccine to cure HPV infection?

We have a vaccine that can prevent HPV infections (a prophylactic vaccine). This vaccine targets HPV’s outer shell (AKA capsid). But HPV's capsid goes away after it gets inside our cells. This is why immunity generated by the vaccine can’t cure HPV infections.

But scientists are hoping to change that and are working on ways to make a vaccine that can cure HPV infections (a therapeutic vaccine). These vaccines aim to generate immunity against HPV E6 and E7, without the need for fancy and expensive cell engineering. Research efforts are currently underway to make these vaccines more potent and effective to treat pre-cancerous lesions, and maybe even cancer more safely and effectively.

Dr. Talia Henkle has distilled 3 research papers, saving your 10.5 hours of reading time

The Science Integrity Check of this 3-min Science Digest was performed by Flávia Oliveira Geraldes.

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