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Hints that Adoptive T-Cell Therapy May Be Promising for Advanced Cervical Cancer

Fuerst, Mark

doi: 10.1097/01.COT.0000455787.41164.85


CHICAGO—Adoptive T cell therapy may provide a new, personalized strategy for advanced cervical cancer, according to a small, federally funded Phase II study reported here at the American Society of Clinical Oncology Annual Meeting (Abstract LBA3008).

In a study among three other abstracts highlighted at an ASCO news conference on progress in immunotherapy, researchers used a personalized immunotherapy approach to treat two patients with widespread metastases, both of whom had complete responses after a single treatment with human papillomavirus (HPV)-targeted T cells, and who at the time of the report had been cancer free for 15 and 22 months, respectively.

The study shows that “adoptive transfer of HPV-targeted T cells can cause complete remission of metastatic cervical cancer and that this remission can be long-lasting,” said the lead author, Christian Hinrichs, MD, Assistant Clinical Investigator at the National Cancer Institute.

One implication of the study is that cellular therapy might have application to a broader range of tumor types than previously recognized. This is the first time adoptive T cell therapy has been tested in cervical cancer. Previously, it has shown promise in melanoma, leukemia, and sarcoma.

Asked for his opinion for this article, Renier T. Brentjens, MD, PhD, Director of Therapeutics and Associate Member in the Leukemia Service at Memorial Sloan Kettering Cancer Center, said, “This proof-of-principle study demonstrates that T cells can root out and get rid of cervical cancer. It is yet another example of the treatment of solid tumor patients with metastatic disease—some of whom, by definition, are incurable. Yet, these researchers were able to expand a viral protein expressed by cervical cancer and completely eradicate the disease.”

Hinrichs cautioned that the treatment is still experimental and is associated with significant side effects—“We also need to explore why this therapy worked so well in certain women, and not in others,” he said.

Metastatic cervical cancer, which is caused by HPV, leads to approximately 4,000 deaths in the U.S. each year. “Chemotherapy is not curative and rarely provides durable palliation,” he said. The median survival with the two standard first-line therapies—chemotherapy and a combination of chemotherapy and bevacizumab—is 13 and 17 months, respectively; and there are no second-line treatments that extend survival.

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HPV Targets

Although the HPV E6 and E7 oncoproteins would appear to be attractive therapeutic targets for immunotherapy, clinical trial results have been disappointing, Hinrichs continued. “Adoptive T cell therapy is an emerging immunotherapy platform, but the study in epithelial cancers has been limited. This is the first example in an epithelial cancer.”



HPV-targeted adoptive T cell therapy essentially augments the natural immune response to HPV in the tumor. A customized treatment was created for each patient by culturing T cells harvested from the patient's tumor, testing the cells for reactivity against the HPV E6 and E7 antigens, and preferentially extracting and then expanding the reactive cultures. The patient then receives a single infusion of tumor-infiltrating lymphocytes, followed with aldesleukin dosed to tolerance.

In the study, nine patients, ranging in age from 30 to 59, received adoptive T cell therapy. Two patients had a complete response and one had a partial response, with a 39 percent reduction in tumor volume, that lasted months; the remaining six patients had progressive disease.

Hinrichs said that one of the complete responders is a 36-year-old woman with HPV16-positive metastatic squamous cell carcinoma of the uterine cervix who had multiple tumor sites and had undergone three different cytotoxic chemotherapy combinations. Her response has now lasted 22 months.

The patient with a complete response had what Hinrichs called a very aggressive primary tumor refractory to chemoradiation and disease that had spread to her pelvis and distant sites. This 36-year-old patient had HPV18-positive adenocarcinoma cervical cancer and had complete regression at all sites, a response that at the time of the report had lasted 15 months.

The treatment was associated with serious side effects, Hinrichs reported. The most common severe adverse events associated with the therapy are hematologic effects that result from the conditioning regimen, which consists of lymphocyte-depleting chemotherapy of cyclophosphamide and fludarabine. All patients had suppressed blood counts and bone marrow counts; and about half of the patients have febrile neutropenia.

“The cells themselves do not seem to cause any autoimmunity,” he noted, adding that all the toxicities are reversible. With only a single infusion, “it's a little bit more tolerable to handle intense toxicities for just one treatment,” he said.

During the question-and-answer period of the news briefing, Hinrichs said this form of adoptive T cell therapy does not pose the danger of generating the “cytokine storm” seen in chimeric antigen receptor (CAR) T-cell therapy. In CAR T-cell therapy, T cells infused into the patient expand and release cytokines that cause fever, hypotension, nausea, and other symptoms that can be severe. The key difference, Hinrichs said, is that the tumor-infiltrating lymphocytes used in HPV adoptive T cell therapy are generated from naturally occurring T cells in the tumor, in contrast to those composed of the genetically engineered T cells used in CAR T-cell therapy.

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Expanded Study

Hinrichs said that with such promising results, the team now plans to recruit 35 patients for an expanded study. The same study is also exploring adoptive T cell therapy for treatment of other HPV-related cancers, such as throat cancer and anal cancer. An increasing number of medical centers working on cellular therapies now offer adoptive T cell therapy, he said.

At his ASCO presentation, Hinrichs concluded: “Durable, complete tumor regression can occur following a single infusion of HPV-targeted tumor-infiltrating T cells. An immunotherapy can induce regression of cervical cancer. Adoptive T cell therapy can mediate regression of an epithelial cancer. Continued study of HPV tumor-infiltrating T cells for patients with metastatic cervical cancer is warranted.”

At the news briefing, the designated ASCO expert, Don S. Dizon, MD, Director of the Oncology Sexual Health Clinic at Massachusetts General Hospital, commented: “Because of the association between cervical cancer and the HPV virus, adoptive immunotherapy is a promising approach. These preliminary data demonstrate not only the viability of this approach, but that gains in survival can be realized in a cancer where patients have little to no effective treatment options and where median survival is usually less than two years.”

Also very positive about the study, the moderator of the news briefing, Steven O'Day, MD, Clinical Associate Professor of Medicine at the University of Southern California Keck School of Medicine, said, “Young women who have failed to respond to chemotherapy can activate T cells and produce a durable response. This approach, well-studied and established in select melanoma patients, can now be moved to the HPV virus to tease out T cells to the virus that provoke a response, expand the T cells, and give the tumor-infiltrating T cells back to the patient. The study has impications for other solid tumors, such as head and neck cancers, as well.”

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Next Steps

Brentjens said that to achieve a higher overall response rate, the researchers will need to identify why some patients did not respond, and correct for that. The low response rate could be due to the quality of the T cells or how long they persist, he speculated. “We can work on fixing such problems by taking the successes and looking at the non-responders to see the differences. How cells are cultured or expanded can have a significant difference in response.



“The success in metastatic cervical cancer bodes well for adoptive immunotherapy moving forward in solid tumors. The goal is to produce a frontline therapy for cancer that one day replaces more toxic chemotherapy.”

To extrapolate this technology to cancers that are not virally induced, however, may be more difficult, he said. “In principle, it should be possible. Where we cannot generate and manipulate a patient's own T cells, another way to overcome the problem may be to use CAR T cells.”

The Discussant for the presentation, John Timmerman, MD, Associate Professor in the Department of Medicine, Hematology/Oncology, at UCLA Jonsson Comprehensive Cancer Center, discussed harnessing immunity to those patients who are challenged by deletion/tolerance of high-affinity T cells. The choice of the tumor antigen is very important, he noted.

“Targeting of a viral or tissue-specific antigen by T cells can lead to durable tumor remissions, with several impressive complete responses in Hinrichs' study. It requires a lot of work to manufacture T cells with the specificity for these well-chosen antigens to achieve the optimal effects.”

© 2014 by Lippincott Williams & Wilkins, Inc.
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