Provenge might have set a rough commercial precedent for immunological cell therapies, but academic investigators have not set this technology aside just yet. Asco has seen release of very early data in advanced HPV-positive cervical cancer, and durable responses in two patients have prompted hope that research in this field will begin anew.
But if the labour-intensive US National Institutes of Health project using targeted tumour infiltrating lymphocytes (TILs) is to be developed, industry will probably not be responsible. “There are an increasing number of centres across the country and in other countries that are working on cellular therapies,” said Dr Christian Hinrichs, an NCI assistant clinical investigator.
The target here is cervical cancer with an origin in human papilloma virus (HPV) infections. First-line patients are typically treated with chemotherapy or a combination of chemo and Avastin, with median survival at 13 and 17 months respectively. No second-line therapies that extend survival are available.
The NIH-sponsored technology is adoptive T-cell therapy, in which the lymphocytes are extracted from the tumour, selected based on a test for reactivity to oncoproteins in cancer cells, expanded outside the body and then reinjected into patients. Patients undergo a single lymphocyte-depleting chemotherapy with fluderabine and cyclophosphamide to prepare their immune systems to accept the new T-cell infusions.
Adoptive T-cell therapy has been tested with some success in melanomas and B-cell cancers, Dr Hinrichs said, but so far it has not been studied much in cancers of epithelial tissues. Dr Hinrichs said the oncoproteins E6 and E7 had been the target of immunotherapy in the past, but without success.
Data unveiled on Monday at Asco came from the first nine patients in a proof-of-principle trial of adoptive therapy, showing that two of the nine achieved complete response to the treatment. At a recent follow-up the two patients showed durability of the complete response at 22 and 15 months.
Adverse events were typical of immunosuppressive therapy in the form of suppressed bone marrow counts and infections; about half the patients experienced febrile neutropaenia or positive blood cultures, Dr Hinrichs said.
“All these toxicities are completely reversible and it’s a one-time therapy so it’s a little bit more tolerable,” he said.
The trial will be expanded to 35 patients to clarify the response rate, while another expansion will add patients with HPV-positive non-cervical tumours such as those in head and neck, oropharyngeal and anal tissue.
In keeping with one of the themes of this year’s Asco, Dr Steven O’Day, clinical associate professor of medicine at the University of Southern California, noted that this was another sign that immunotherapies were displaying a wider range of applicability than originally thought.
“We’re using these oncoproteins of the HPV virus to tease out the T-cells to which the virus particles provoke a response,” Dr O’Day said. “It’s a very exciting approach to a cancer that really has not been an immunological target.”
And, along a second theme of Asco, this approach appears to be dependent on the largesse of finite government resources at the NIH along with academic medical centres.
It is not especially surprising to see this in the hands of academic researchers – after all, there are many parallels to Dendreon’s disappointing Provenge in that it is an autologous immunotherapy that requires ex vivo culturing and expansion before re-infusion. Provenge was once forecast to achieve multi-billion-dollar sales this year, but current estimates put it at $321m, growing to $519m in 2020, according to EvaluatePharma’s consensus.
One of Provenge’s many problems has been manufacturing, and, given how Dendreon’s bubble deflated with the disappointing launch, investors could be wary of any company exploring such a technology.
This will be no less difficult for the government and academic centres, but oncologists urged expansion of research because of the potential of a treatment that might extend survival with a limited duration of side effects. “The best we have commits women to chemotherapy or a biological for the rest of their lives,” said Dr Don Dizon, gynecologic oncology specialist at Massachusetts General Hospital.
“If we at all these academic centres can standardise this approach and identify the patients who are most likely to benefit, we can really reduce deaths from this disease … and given women back their lives. If they’re in this situation they should seek out this federally funded trial at the NCI,” Dr Dizon said.
Dr O’Day added that this early work could also help developers identify less complex approaches using the same targets.
“The science is trying to make that more efficient. Can we in vivo manipulate some cells without doing a lot of ex vivo work?” he said. “The science is exciting and it’s giving us an opportunity to direct the immune system [at a tumour] that traditionally isn’t seen by the immune system.”
|HPV-targeted tumour-infiltrating lymphocytes for metastatic cervical cancer||NCT01585428|