Breakthroughs in Cell Therapy: A New Era for HPV-Related Cancer Treatment

At the 2025 Society for Immunotherapy of Cancer (SITC) Annual Meeting in National Harbor, Maryland, researchers unveiled striking results from 2 landmark phase 2 trials of cell therapies. The findings suggest that onetime cell therapies could fundamentally reshape the treatment landscape and prognostic outlook in difficult-to-treat human papillomavirus (HPV)–associated epithelial cancers, offering durable responses, potential for lasting remission, and new hope for patients.¹

The first study (NCT01585428) reported an impressive 10-year follow-up of 2 patients with metastatic cervical cancer treated with autologous tumor-infiltrating lymphocyte (TIL) therapy. One decade after receiving a single infusion of TIL therapy, both patients remain in complete remission, suggesting long-term, potentially curative immune control of their disease.^2,3

At the same time, interim results from an ongoing study (NCT05686226) administering genetically engineered T cell receptor (TCR)–T cells to patients with a broad range of metastatic HPV-associated cancers—including head and neck cancer, cervical cancer, anal cancer, and esophageal cancer—demonstrated robust antitumor activity.^4,5 Remarkably, several patients experienced deep responses after a single infusion, indicating the potential emergence of a new generation of cell therapy.

Christian S. Hinrichs, MD, codirector of the Cancer Immunology and Metabolism Center of Excellence at Rutgers Cancer Institute and lead investigator of the 2 studies, spoke with Targeted Oncology^® about the significance of the findings and implications for integrating these novel cell therapies into clinical practice.

Targeted Oncology: Could you summarize the background, methods, and key takeaways of the TIL therapy study presented at SITC?

Christian S. Hinrichs, MD: The first study was a treatment of TIL therapy for HPV-associated cancers. This is an autologous cell therapy, where the treatment cells are derived from the patient's own tumor, generated in the lab, and returned to the patient. The study was a phase 2 study for HPV-associated cancers from any primary tumor site.

What was presented at the SITC meeting was the follow-up on 2 patients from the original phase 2 study who had complete responses in metastatic cervical cancer. They received a onetime TIL infusion and initially had complete responses. Ten years later, we studied them to see if they remained disease free. What we saw was that, by imaging and circulating cell-free tumor DNA, they continued to have no evidence of disease.

There were other translational research analyses that were done as part of that study. [In] one, we sought to understand the antitumor T-cell responses and how much persistence of the therapeutic T cells was required to achieve these responses. We were able to track the tumor antigen-specific T-cell clonotypes based on prior research that we had done, identifying the tumor antigen-specific T-cell clonotypes from each of those 2 patients with complete responses. What we saw was the tumor regression was fairly rapid, occurring in weeks to months. And in that early period of tumor regression, there was expansion of the tumor antigen-specific T-cell clonotypes, but those cells peaked in peripheral blood and came down to at or below baseline levels by 1 to 2 years, while the antitumor responses are still ongoing more than 10 years later.

What this suggests is that a burst or expansion of the antitumor T cells early in that 10-year window and then reducing to below baseline levels after 1 to 2 years was sufficient for the long-term responses. This starts to address, at least to some extent, the question of whether a T-cell response is needed to clear the tumor initially and then that T-cell response can go away, or if we need to have ongoing presence of the antitumor T cells for immune surveillance and to control the tumor indefinitely. This points more toward a model where the tumor is cleared and the T cells largely go away.

It does have limitations. We're only able to study the T cells in the blood. Of course, we can't study them in the tumor because there's no detectable tumor. But we don't know for certain if there's micrometastatic disease or some standoff at that level. But the general direction it seems to point [toward] is more of a clearance of the tumor and then a contraction of the antitumor T cell response.

Could you summarize the background, methods, and findings of the study on TCR-T cell therapy presented at SITC?

The other study is what we would consider a next-generation approach after the TIL, which is an effort to genetically engineer peripheral blood T cells to be able to target these HPV-associated cancers. This approach is like a CAR T approach in that it uses autologous peripheral blood T cells that are gene-engineered ex vivo with a receptor that lets them target the tumor, and the cells are expanded to large numbers and administered back to the patient.

The difference is that instead of using a chimeric antigen receptor—which, generally speaking, is going to be designed to target a tumor antigen on the cell surface—here, we use a [TCR], which is designed to target an intracellular antigen that's processed and presented intracellularly, presented by an HLA-A2 molecule, and then recognized by the T cell as an epitope or fragment of that target protein presented by an HLA-A2 molecule. The target antigen is HPV16 E7—the specific epitope is E7 11-19—and that is presented to T cells by the HLA-A201 molecule.

This study was a phase 2 study for HPV-associated cancers, any primary tumor site, after first-line therapy. We've treated 10 of 20 planned patients in an ongoing phase 1 [trial]. There were responses in 6 of the 10 patients, [meaning] partial response or complete response by RECIST criteria. Two of the responses are complete responses, and both are ongoing, one at 12 months and one at 14 months after treatment. Both responses are in patients with metastatic disease that were refractory to combination chemotherapy plus checkpoint inhibitor. They had very limited treatment options at the time they were treated on the trial.

What insights can you offer to community oncologists on identifying patients who might benefit from referral to institutions offering such specialized cell therapies in clinical trials?

A number of things come to mind, and it's a little bit challenging, because I don't necessarily think I can speak for everyone in the field who's trying to do these at an academic center, so some of this will be my point of view. My preference is to receive referrals for patients early, because it can take quite a while to work them up to see if they're eligible. Patients like to know what they're going to do next, because generally speaking, the types of treatments they're receiving for metastatic disease are not going to be expected to be curative. It just makes sense for everybody to start lining up the treatment option early, and there's really nothing substantial lost by trying to determine eligibility early and seeing if it's an option. [There’s] a lot to be gained by lining things up so that time is not lost.

Another personal point of view is that in all of oncology, treatments work better in earlier lines of therapy, and it's somewhat remarkable that we've seen results as good as they are in our phase 2 trial in what is essentially or approaching a last-line setting. I think that it's going to be important for the field to try to move these treatments up to an earlier line of treatment. It's important for these patients to have a chance at this [type] of trial that is designed as a onetime treatment, and seems to offer the hope, at least in some patients, for a durable response before they get to the point where they have exhausted every possible treatment—including those that are unlikely to be beneficial, and where their performance status and chance of participating in these trials safely and getting a good result is starting to diminish.

Another point from the [stand]point of our program, especially for the HLA-restricted treatments like the E7 TCR, [is that] there is a screen fail[ure] rate due to the targeted nature of the treatment and the [corresponding] molecular requirements. The patient has to have an HPV16 genotype cancer and an HLA-A2 molecule. Putting those 2 gates together results in about 20% or 25% of patients potentially being eligible. There is inherently a screen fail[ure] rate in doing these trials.

But really, this is seen, I think, across oncology. As our drugs get more and more targeted, you do need to screen more patients to find patients who are eligible. From our point of view, we are delighted to screen patients, and we know that screening is just part of doing business. If a patient is not eligible, we're still energized to screen the next patient. For community physicians who are thinking about this [type] of trial for their patient, it can get discouraging, because the patients are often not going to qualify, but they should know that we're energized to keep going, and we hope they are too.

I think one of the things that can be daunting is trying to figure out if your patient is eligible, and at least for our system here, if anyone calls or emails me, I forward it to a team who will get back to the patient within 24 hours and start gathering the information we need to know about eligibility. Our system is designed around taking that burden [from the referring physician] of knowing all the eligibility criteria and knowing how to do tests that one might not be familiar with because they're not a part of standard oncology practice. If it's OK with the referring physician, we will connect with them in their office, or with the patient, whatever they prefer, and try to take care of it.

Comprehensive cancer centers like Rutgers Cancer Institute possess the scientific resources necessary to translate clinical benefits from bench to bedside. What is your prediction regarding the future distribution and delivery model of these highly specialized treatments in local settings?

The future is a notoriously difficult thing to predict. [For] the treatments that we're developing, you can think of them much like CAR T cells and the TIL [therapy] for HPV-associated cancers that's being developed by Iovance Biotherapeutics, the same company that's developing TIL for metastatic melanoma. The treatments that we're developing will follow, I think, in the model of other cell therapies that are going before us. And this is not my area of expertise, but my impression is that, especially with the CAR Ts, this is starting to move more toward community centers and efforts to offer that type of treatment more broadly and safely. I don't have a crystal ball on exactly how this is going to go, but I think it'll basically follow the same model evolution as the CAR T-cell approaches.

REFERENCES

1. Landmark data from Rutgers Cancer Institute and RWJBarnabas Health show long-term complete responses of T cell therapies for HPV-related cancers. News release. Rutgers Cancer Institute. November 7, 2025. Accessed November 14, 2025. https://tinyurl.com/bdf5wha9

2. Norberg SM, Doran S, Subramanian K, et al. 377 Decade-long epithelial cancer remissions from cellular therapy. JITC. 2025;13(suppl 2):A429-A429. doi:10.1136/jitc-2025-SITC2025.0377

3. Immunotherapy using tumor infiltrating lymphocytes for patients with metastatic human papillomavirus-associated cancers. ClinicalTrials.gov. Updated March 7, 2018. Accessed November 14, 2025. https://clinicaltrials.gov/study/NCT01585428

4. Norberg SM, Doran S, Cao J, et al. 366 Complete tumor regression of metastatic epithelial cancer following T cell receptor (TCR)-T cell therapy. JITC. 2025;13(suppl 2):A417-A417. doi:10.1136/jitc-2025-SITC2025.0366

5. E7 TCR-T cell immunotherapy for human papillomavirus (HPV) associated cancers. ClinicalTrials.gov. Updated March 30, 2025. Accessed November 14, 2025. https://clinicaltrials.gov/study/NCT05686226