This is the original study where all the "hoopla," if I may use "salty" language, arose. Though the title is rather nondescript, the result is promising. I'll annotate this in the body of the text. It's a fascinating result, but curb your enthusiasm for now, there's a lot yet to do.
Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations—such as melanoma, smoking-induced lung cancers and bladder cancer—with little effect in other common epithelial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary1,2,3,4,5,6,7. Adoptive transfer of autologous lymphocytes that specifically target proteins encoded by somatically mutated genes has mediated substantial objective clinical regressions in patients with metastatic bile duct, colon and cervical cancers8,9,10,11. We present a patient with chemorefractory hormone receptor (HR)-positive metastatic breast cancer who was treated with tumor-infiltrating lymphocytes (TILs) reactive against mutant versions of four proteins—SLC3A2, KIAA0368, CADPS2 and CTSB. Adoptive transfer of these mutant-protein-specific TILs in conjunction with interleukin (IL)-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer, which is now ongoing for >22 months, and it represents a new immunotherapy approach for the treatment of these patients.
This is a patient with metastatic breast cancer who did not respond to chemotherapy (“chemorefractory”). This is a disease that is generally considered treatable but not curable, and patients with chemorefractory disease are often considered terminally ill.
This patient was treated with immune cells (tumor-infiltrating lymphocytes) that were specifically “trained” against mutated proteins only found in the cancer cells (SLC3A2, etc). The researchers tossed in some other “helper” meds, including the immune cell controller interleukin 2 and a “Checkpoint Blockade” (another facet that essentially takes the gloves off of parts of the immune system) medication.
The result was a “complete, durable regression” (i.e., “cure”) which has held for greater than 22 months. They won’t call it a true “cure” until 5 years out. We’re so used to cancers like this being incurable that the term complete regression seems more palatable to oncologists. Hopefully in the future, the language will change as we see real “cures” for this kind of disease.
This is “only” one patient, but if it’s reproducible, this will add another large chunk of ammunition in the war against cancer.
yr obt svt,
Steve
Two Infants Treated with Universal Immune Cells Have Their Cancer Vanish
In a medical first, the children were treated with genetically engineered T-cells from another person.
by Antonio Regalado January 25, 2017
Doctors in London say they have cured two babies of leukemia in the world’s first attempt to treat cancer with genetically engineered immune cells from a donor. The experiments, which took place at London’s Great Ormond Street Hospital, raise the possibility of off-the-shelf cellular therapy using inexpensive supplies of universal cells that could be dripped into patients’ veins on a moment’s notice.
The ready-made approach could pose a challenge to companies including Juno Therapeutics and Novartis, each of which has spent tens of millions of dollars pioneering treatments that require collecting a patient’s own blood cells, engineering them, and then re-infusing them.
Both methods rely on engineering T cells—the hungry predator cells of the immune system—so they attack leukemic cells.
The British infants, ages 11 and 16 months, each had leukemia and had undergone previous treatments that failed, according to a description of their cases published Wednesday in Science Translational Medicine. Waseem Qasim, a physician and gene-therapy expert who led the tests, reported that both children remain in remission.
Although the cases drew wide media attention in Britain, some researchers said that because the London team also gave the children standard chemotherapy, they failed to show the cell treatment actually cured the kids. “There is a hint of efficacy but no proof,” says Stephan Grupp, director of cancer immunotherapy at the Children’s Hospital of Philadelphia, who collaborates with Novartis. “It would be great if it works, but that just hasn’t been shown yet.”
Rights to the London treatment were sold to the biotech company Cellectis, and the treatment is now being further developed by the drug companies Servier and Pfizer.
Treatments using engineered T-cells, commonly known as CAR-T, are new and not yet sold commercially. But they have shown stunning success against blood cancers. In studies so far by Novartis and Juno, about half of patients are permanently cured after receiving altered versions of their own blood cells.
But commercializing such personalized treatments raises unprecedented logistical headaches. Grupp says Novartis has outfitted a manufacturing center in New Jersey and that patient cells have been flown in from 25 hospitals in 11 countries, modified, then quickly shipped back. Novartis has said it will seek U.S. approval to sell its T-cell treatment for children this year.
The promise of immunotherapy has drawn huge investments, yet many newer entrants are betting instead on the off-the-shelf approach. Among them are biotech giant Regeneron, Kite Therapeutics, Fate Therapeutics, and Cell Medica.
“The patient could be treated immediately, as opposed to taking cells from a patient and manufacturing them,” says Julianne Smith, vice president of CAR-T development for Cellectis, which specializes in supplying universal cells.
In the off-the-shelf approach, blood is collected from a donor and then turned into “hundreds” of doses that can then be stored frozen, says Smith. “We estimate the cost to manufacture a dose would be about $4,000,” she says. That’s compared to a cost of around $50,000 to alter a patient’s cells and return them.
Either type of treatment is likely to cost insurers half a million dollars or more if they reach the market.
Robert Nelsen, a venture capitalist and a founder of Juno Therapeutics, which raised hundreds of millions for the custom approach, says he’s not worried about companies developing universal alternatives. “What they can do in the future is what we can do today,” Nelsen said in an interview last year. “And I guarantee you even if things were equal, which they are not, you would want your own stuff, not someone else’s cells.”
The London treatment is notable for involving the most extensively engineered cells ever given to a patient, with a total of four genetic changes, two of them introduced by gene editing using a method called TALENs. One alteration was to strip the donor cells of their propensity to attack the body of another person. Another directs them to attack cancer cells.
In the U.S. and China, scientists are also racing to apply gene editing to make improved treatments for cancer and other diseases.
by David Kroll on Forbes.com
An engineered version of the poliovirus has been in development for more than 20 years as a treatment for one of the most difficult-to-treat cancers, a brain tumor called glioblastoma multiforme, abbreviated GBM. A human safety trial of the virus, called a Phase I study, is ongoing at Duke University’s Brain Tumor Center in Durham, North Carolina. The patients who’ve been enrolled have the toughest form of this disease: GBM that has returned after previous surgery and treatment.
Last night, the CBS News program 60 Minutes devoted two segments of the broadcast to correspondent Scott Pelley’s 10-month-long glimpse into this clinical trial. (Disclosure: I have held an unpaid adjunct faculty appointment in Duke University’s Department of Medicine since 2002, was a paid faculty member there in 2001, and did a year-long research sabbatical there in 2000 while I was a pharmacy professor at the University of Colorado.)
The segment, called “Killing Cancer,” was produced by Michael Radutzky and Denise Schrier Cetta and did a responsible job of illustrating the potential power of this new treatment with the sober realities of the challenges presented by a cancer whose prognosis is measured in months. The program, the entire transcript, and supplementary materials are available at the 60 Minuteswebsite.
Using the virus that causes the childhood paralytic disease called poliomyelitis to treat cancer seems outrageous. We’ve been trying to eradicate the virus from the planet since the 1950s, when two types of vaccines were developed by Drs. Jonas Salk and Albert Sabin. The Americas were declared polio-free in 1994 and the disease only remains in three countries: Nigeria, Pakistan, and Afghanistan.
But the way that the polio virus infects cells and what it does afterwards are the precise actions that Matthias Gromeier, MD, thought could be harnessed to treat cancer. Gromeier has been at Duke for the last 15 years painstakingly shepherding his studies from lab to clinic. But the German-trained molecular biologist began this work in earnest 25 years ago when he came to the States to work with the renowned virologist, Eckard Wimmer, at the State University of New York at Stony Brook.
Some technical background
Detailed in this seminal 1996 paper in the Proceedings of the National Academy of Sciences, Gromeier and colleagues in Wimmer’s lab replaced a segment of the poliovirus’s RNA genome with a corresponding piece from a human rhinovirus, a type that causes the common cold. (The virus is still known in the literature and on Duke’s webpage by the cumbersome name, PVS-RIPO.)They found that this recombinant (or chimeric) virus could still infect cells that had the poliovirus receptor, but that the virus didn’t replicate. Many cancer cells, including glioblastoma, overproduce the poliovirus receptor (known as CD155 or Necl-5). So, by using the right amount of this designer virus, the researchers could selectively kill glioblastoma cells in culture without affecting normal neuronal cells. For this reason, this virus is called an oncolytic virotherapy, meaning that it causes lysis or bursting open of cancer cells.
But that’s not all. The way that cancer cells make proteins is different from that of normal cells. So even when the virus gets into some normal cells that have the receptor, it’s not as damaging. This two-part difference between cancer cells and normal cells is the basis for trying to treat human glioblastomas by directly infusing very small amounts into the tumor through a one millimeter diameter catheter that’s inserted into the tumor through the skull, guided by 3-D imaging. That part of the work is done by Duke neurosurgeon, John Sampson, MD.
But once in the brain, the virus triggers the body’s immune response against the tumor cells. In fact, the patient’s own immune response is probably more important than the initial bursting of the cancer cells.
As Gromeier explained on 60 Minutes, “So cancers, all human cancers, they develop a shield or shroud of protective measures that make them invisible to the immune system. And this is precisely what we try to reverse with our virus. So by infecting the tumor, we are actually removing this protective shield. And telling the– enabling the immune system to come in and attack.”
But the immune response must be carefully manipulated because too much virus can cause a massive swelling of the brain. So that’s why the goal of this first Duke trial isn’t to determine the virus’s effectiveness. The purpose is to get to the right dose, as explained by the Brain Tumor Center’s deputy director, Henry Friedman, MD.
A personal aside
While I was on sabbatical at Duke in 2000, Gromeier had joined the faculty in microbiology and immunology in the same building where my mentor, Ken Kreuzer was located. I remember when Gromeier’s first independent grant was funded through the National Cancer Institute’s RAID program, a mechanism that allowed unique cancer treatments discovered in academia to be cultivated for clinical trials using the preclinical toxicology, medicinal chemistry, and biologics expertise of the NCI Developmental Therapeutics Program to produce the clinical trial-quality viral study agent.
When I ran into Gromeier again a few years into the process, he said that the level of detail required to get the product even made was tortuous. When they were using cholesterol in the mix to originally help the virus into the cells, he said that NCI and FDA were concerned about the source of the cholesterol being cattle and that they had to be sure that the preparation didn’t have any miniscule amount of the virus that causes mad cow disease. Every step of the process had to overcome this degree of scrutiny. And even when the clinically-qualified batches of virus were made, the FDA required seven more years of safety testing, up to and including administration to three dozen monkeys, before the first human subject was permitted in 2011.
My near-teenage daughter just walked past the computer as I’m writing this and I was struck by the fact that Gromeier has been working on this at Duke a couple of years longer than she has been alive. The rigor with which the safety of this approach is being evaluated is remarkable.
I encourage you to watch both parts of the 60 Minutesstory. Knowing some of the folks involved but also putting on my critical hat as a scientist and writer, I have a few thoughts on how the story was presented.
What I liked:
1. The program was careful to note that the effectiveness of the virus in three of the study volunteers interviewed was offset by an equal number of patients who are no longer alive. Eleven of the 22 volunteers have succumbed to their disease.
2. The program gave time for Henry Friedman to say that a clinical effect of the study agent is not the goal of a Phase I study.
3. Annick Desjardins, MD, the neurooncologist who followed the patients and evaluated their post-surgical functioning, showed the true level of compassion and teamwork that forms the nucleus of the Brain Tumor Center’s reputation.
4. Even when Scott Pelley pushed Friedman and center director, Darell Bigner, MD, PhD, to use the word “cure” or “miracle,” both were very measured and guarded but still conveyed a sense of optimism. In Friedman’s 34 years at Duke and Bigner’s 49 years, they’ve seen a lot of death. But they’ve also made significant contributions globally in the treatment of brain cancers. So for them to both say that the recombinant poliovirus approach was the most promising agent they’ve seen for glioblastoma in their careers, it’s hard not to be excited.
5. Both the program and Duke made it very easy for prospective patients to have their questions answered about potential eligibility for the trials: Editor’s Note: For more information on the Duke University polio trial or other brain cancer trials, click here or call 919-684-5301. The Duke page is very easy for interested subjects to navigate for referrals and information on this and other clinical trials at the Brain Tumor Center. The site was clobbered last night and was unreachable for the first two hours after the program aired, but it has been available every time I’ve clicked this morning.
What I liked less:
1. At the outset, Pelley made it sound like very few advances have been made in cancer treatment over the last 100 years: “The long war on cancer has left us well short of victory. Radiation flashed on in the 19th century, chemotherapy began to drip in the 20th but, for so many, 100 years of research adds up to just a few more months of life.” That’s partly true, but partly nonsense. Tremendous strides have been made within many cancers, from childhood leukemia cures to cancer survivors who are counting decades since their treatment. The program needn’t have denigrated how far we’ve come to show the promise of the viral therapy. It’s impressive enough on its own.
2. Pelley: “Duke went to the FDA for approval of this new Frankenstein virus.” Frankenstein? No, no, no, no. Moreover, the virus wasn’t approved. It was granted Investigational New Drug status to begin clinical trials.
3. The emotional power of the two people who are in remission, particularly the first recipient, Stephanie Lipscomb, was so positively overwhelming that I don’t think the risks were fully balanced by the story of another patient who did not do well and withdrew from the study. The positive anecdotes were very compelling and a viewer hoping to get into subsequent trials might be overly optimistic. While I mentioned above that I liked the fact the the 11 of 22 response statistics were a valuable inclusion, the amount of time given to that point led to its underrepresentation.
4. For Forbes readers, there was a paucity of information on the intellectual property considerations of the polio virus therapy and detail on how the drug will ultimately be commercialized. The program mentioned briefly that the investigators have a financial stake in the drug’s success, as with many clinical trials. But there was no discussion of the fact that the first patents on the therapy were granted to Gromier with Wimmer and the Research Foundation of SUNY-Stony Brook. Issued in 2003 and 2006, we don’t know if any hurdles exist for Duke’s commercialization of the technology (I have no inside information on this; I’m just raising it as a viewer who expected the issue to be addressed.).
5. While interviewing Gromeier, Pelley led him to speak about the use of the virus against other cancers. I don’t think the program made clear that the work in prostate, breast, and pancreatic cancer, among others, was still in the experimental phase.
6. The program only briefly touched on other therapies that exploit the immune system for cancer but didn’t mention that viral approaches are being taken by quite a few other research teams and companies. Forbescontributor, Arlene Weintraub, has a more comprehensive discussion this morning.
7. Without knowing Henry Friedman, one might think that CBS was being disrespectful to him because he chooses not to dress as a typical physician: He was wearing a Duke hoodie and jeans and Pelley said that’s how Friedman’s brain thinks about fashion. Indeed, his dress is most often casual but I know that it breaks down barriers with his patients, most who are coming from far away and freaked out about their disease. Friedman is a fierce advocate of every facet of Duke and has contributed immensely to the brain cancer treatment internationally. Moreover, I admire him most for his establishment of a program (with neurosurgery colleague, Allan Friedman, MD – not related) for Duke’s women athletes who wish to pursue medical school and his strong support of Duke women’s basketball. Perhaps that’s just me.
Why the absence of the Tisch name?
And my final observation was one that just struck me as odd. The Duke Brain Tumor Center, originally established in 1937, was renamed the Preston Robert Tisch Brain Tumor Center after the Tisch family donated $10 million for research at the Brain Tumor Center and the Duke Comprehensive Cancer Center. Yet the 60 Minutes program made no mention of this name.
The late Bob Tisch was treated at Duke for his brain cancer, living for 14 more months after he was given a two-month prognosis in New York. Bob Tisch was the brother of the late Larry Tisch, CEO of the CBS network from 1986 to 1995. During his tenure, Larry Tisch slashed jobs in the news division and one can’t help but think that the remaining old-timers at 60 Minutes might hold some grudge. Alternatively, they might not have wanted to cloud the story with this two-steps-removed association with the Duke Brain Tumor Center.
In any case and for whatever reason, the omission was glaring. CBS has not responded to a request for information.
From Sky News
Tests of a potentially revolutionary cancer therapy have had “extraordinary” results on terminally ill patients, scientists have revealed.
In one study, more than nine out of ten participants with a severe form of leukaemia saw their symptoms completely vanish.
Four out of five patients with some other blood cancers responded positively to the treatment and more than half ended up symptom free.
Lead scientist Professor Stanley Riddell, from the Fred Hutchinson Cancer Research Center in Seattle, US, said the results were among patients who were projected to have two to five months to live.
He said: “This is extraordinary. This is unprecedented in medicine to be honest, to get response rates in this range in these very advanced patients.”
The technique involves removing immune cells called T-cells from patients, tagging them with “receptor” molecules that target cancer, and putting them back into the body in an infusion.
The targeting molecules, known as chimeric antigen receptors or Cars, came from specially bred genetically engineered mice.
Once attached to the T-cells, they reduce the ability of the cancer to shield itself from the body’s natural immune system.
Speaking at the American Association for the Advancement of Science (AAAS) annual meeting in Washington DC, Prof Riddell described the results as a “potential paradigm shift” in cancer treatment.
Much more work was required, he said, adding that it was not clear how long the symptom-free patients would remain in remission.
Prof Riddell hopes to try the therapy on patients suffering from cancers with solid tumours, but said they would present challenges.
Although the body’s natural immune system is geared to tackle cancer, it is often unable to. Sometimes, the body’s defences cannot recognise cancer cells or they find ingenious ways to mask their identity.
In the most promising of Prof Riddell’s studies, around 35 patients with acute lymphoblastic leukaemia (ALL) were treated with the modified cells.
Almost all – 94% – went into complete remission. Being in remission is not the same as saying they are cured, because the symptoms can return.
Here, medics are urging caution. Dr Yvonne Doyle, from Public Health England, said: “It’s an important breakthrough, in that it’s a new technology that seems to have developed something innovative.
“However, it is on 30 patients who are at a very advanced stage of a particular cancer. So what we need to know is does this work in a wider situation?”
The treatment is similar to a technique used with success last year on Layla Richards, a one-year-old girl with ALL, by doctors at Great Ormond Street Hospital, who described the results as “staggering”.
A consultant immunologist who treated Layla, Professor Waseem Qasim, told Sky News it was still early days: “We will have to wait and see how these type of treatments play out for solid cancers such as cancers of the lung or the bowel or the breast and so on…
“The first tranche of investigations and successes I think will be in the blood-type cancers.”
[Though not as striking as the abscopal effect stories that have come out recently in the context of metastatic melanoma, this story advances the notion that immune modulation is a viable approach to a generalizable treatment for cancer. Although my hypothesis is that patient specific immune modulation (targeting the patient’s actual tumor markers and pointing the immune system in the right direction) will be the eventual answer, drug companies want to at least try to develop something general that they can sell. We’ll see if this approach is just a stepping stone to a more complete general treatment or if they actually figure something out. In the meantime, this is a very interesting bit of news. –dr steve]
(CNN)Researchers meeting in Chicago are hailing what they believe may be a potent new weapon in the fight against cancer: the body’s own immune system.
An international study found that a combination of two drugs that helped allow the immune system to fight the cancer — ipilimumab and nivolumab — stopped the deadly skin cancer melanoma from advancing for nearly a year in 58% of the cases.
Melanoma, though a skin cancer, can spread to the lungs, liver, bone, lymph nodes and brain.
Other studies have shown promise in treating lung cancer. The research is being presented in Chicago at the annual conference of the American Society of Clinical Oncology and published in The New England Journal of Medicine.
Those involved in the fight against cancer are divided as to just how excited to get over the promise of immunotherapy in battling cancer.
“Immunotherapy drugs have already revolutionized melanoma treatment, and now we’re seeing how they might be even more powerful when they’re combined,” said Dr. Steven O’Day, an expert with the American Society of Clinical Oncology.
“But the results also warrant caution — the nivolumab and ipilimumab combination used in this study came with greater side effects, which might offset its benefits for some patients. Physicians and patients will need to weigh these considerations carefully,” O’Day said.
In the study, 36% of the patients receiving the two-drug combination had to stop the therapy due to side effects. Both drugs are made by Bristol-Myers Squibb, the sponsors of the study.
And Nell Barrie, a spokeswoman for Cancer Research UK, while calling the results “encouraging” and “promising,” told CNN that much remains to be learned and the new drugs would not replace any of the existing cancer treatments.
Surgery, she said, would remain vital. So, too, would chemotherapy and radiotherapy, she said.
She noted that researchers had yet to study the long-term survival rates for immunotherapy. And the side effects can include inflammation of the stomach and bowel serious enough to require hospitalization, she said.
But Dr. James Larkin, the lead author of the melanoma study, called the results a game changer.
“We’ve seen these drugs working in a wide range of cancers, and I think we are at the beginning of a new era in treating cancer,” Larkin told The Telegraph, a British newspaper.
Barrie said immunotherapy could offer hope to people with cancers that are otherwise difficult to treat, such as melanoma, advanced lung cancer or cancer that has spread throughout the body.
“We’re looking at another weapon in the arsenal,” she said.
At the heart of immunotherapy is that cancer — unlike most other diseases — is not an invader. It consists instead of the body’s own cells gone rogue.
So the immune system is not programmed to target the cancerous cells because it does not recognize them as foreign.
The immunotherapy drugs, Barrie said, “work to switch the immune system back on.”
[This one is a rare effect, but if they can just figure out how to trigger it consistently (research is ongoing) this would be a kickass weapon in the war against malignant melanoma and some other cancers. A more general article on the abscopal effect can be found on Wikipedia, but here’s a quickie from Oncology Nurse Advisor. –dr steve]
A recent melanoma case featuring the abscopal effect, in which local radiotherapy delivered to a single tumor results in the regression of metastatic cancer at a distance from the irradiated site, may lay the groundwork for a promising approach to melanoma treatment.
Although the abscopal effect is extremely rare, it has been described in several cases of melanoma, lymphoma, and kidney cancer, according to a statement from Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, New York. MSKCC medical oncologist Jedd Wolchok, MD, PhD, was senior author of the report describing the recent case (N Engl J Med. 2012;366-925931).
“We are excited about these results, and what we have seen in this one patient proves the principle that adding radiation therapy to immunotherapy may be a promising combination approach to treatment for advanced cancer,” commented Wolchok.
Wolchok’s team used ipilimumab, an immunotherapy, to treat a patient with advanced melanoma. Approved by the FDA in March 2011, ipilimumab is the first drug to demonstrate improved overall survival in persons with advanced melanoma. This monoclonal antibody works by inhibiting an immunologic checkpoint on T cells known as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4).
Over time, Wolchok’s patient’s melanoma had metastasized to the spleen, lymph nodes, and near the spine. When localized radiation was administered to the tumor near the spine to provide pain relief, the targeted tumor shrank significantly—and, unexpectedly, so did the tumors in the spleen and the lymph nodes, even though those sites were not directly targeted by the radiation therapy. The use of radiation therapy also resulted in other changes that allowed the patient’s immune system to recognize and control the cancerous cells more effectively.
The researchers followed the patient from her initial diagnosis of melanoma in 2004 through a series of treatments and eventual disease regression in April 2011 after a combination treatment of radiation and immunotherapy.
[Another interesting idea…if you know someone with refractory multiple myeloma, they may qualify for a clinical trial in vaccine therapy (take THAT, anti-vaxxers!) –dr steve]
from cnn.com
A woman with an incurable cancer is now in remission, thanks, doctors say, to a highly concentrated dose of the measles virus.
For 10 years, Stacy Erholtz, 49, battled multiple myeloma, a deadly cancer of the blood. Doctors at the Mayo Clinic say she had received every type of chemotherapy drug available for her cancer and had undergone two stem cell transplants, only to relapse time and again.
Then researchers gave her and five other multiple myeloma patients a dose of a highly concentrated, lab-engineered measles virus similar to the measles vaccine. In fact, the dose Erholtz received contained enough of the virus to vaccinate approximately 10 million people.
“The idea here is that a virus can be trained to specifically damage a cancer and to leave other tissues in the body unharmed,” said the lead study author, Dr. Stephen Russell.
It’s a concept known as virotherapy, and it’s been done before. Mayo Clinic scientists say thousands of cancer patients have been treated with viruses, but this is the first case of a patient with a cancer that had spread throughout the body going into remission.
Erholtz was cancer-free for nine months.
“I think we succeeded because we pushed the dose higher than others have pushed it,” Russell said. “And I think that is critical. The amount of virus that’s in the bloodstream really is the driver of how much gets into the tumors.”
In simple terms, the measles virus makes cancer cells join together and explode, Mayo Clinic researcher Dr. Angela Dispenzieri explains. There’s also some evidence to suggest, she says, that the virus is stimulating the patient’s immune system, helping it recognize any recurring cancer cells and “mop that up.”
This treatment is still in the early testing stages, though. Doctors recently used radiation therapy to treat a small, localized tumor in Erholtz’s body.
And the other patients in the trial did not go into remission. Tests showed the virus helped shrink one woman’s tumors, but they started growing again soon after. The other patients’ cancers did not respond to the treatment.
Researchers also don’t know whether this virotherapy will help other patients or whether it can be applied to other types of cancer. The measles virus worked with these multiple myeloma patients because they are already immune-deficient, meaning their bodies can’t fight off the virus before it has a chance to attack the cancer cells.
More of the highly concentrated measles virus is being created now to be used in a larger clinical trial, Mayo Clinic researchers say. They’ve developed a manufacturing process that can produce large amounts of the virus, Russell says.
“We recently have begun to think about the idea of a single shot cure for cancer — and that’s our goal with this therapy,” he said.
[I used to say we were 100 years away from a more generalized approach to cancer therapy. In the end, barring some unforeseen breakthrough, cancer “cures” will come from the realm of immunology. The immune system is perfectly appointed to eradicate cancer cell by cell, molecule by molecule, but it only works if it actually recognizes the cancer as abnormal. Turning on the immune system to recognize cancer cells as foreign is the purpose of a lot of research right now and this is the outcome of a small pilot study. This makes me think the time horizon is much less than 100 years. Stay tuned for more; I’ll post new articles as I find them. –Dr Steve]
CHICAGO ? The data are preliminary, but the results are striking, demonstrating that an immunotherapy approach using adoptive T-cell therapy may have a role in the treatment of advanced cervical cancer.
A single infusion of the T-cell therapy induced a complete and durable remission in 2 patients with advanced metastatic cervical cancer. In addition, a third patient achieved a partial response of 3 months’ duration, with a 39% reduction in tumor volume.
“This study shows that complete and durable tumor regression can occur following a single infusion of HPV [human papillomavirus]–targeted tumor-infiltrating T cells,” said lead study author Christian Hinrichs, MD, an assistant clinical investigator at the National Cancer Institute.
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Dr. Christian Hinrichs
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As of last week, he noted, the 2 patients remain in complete remission and are now at 15 and 22 months after treatment.
Speaking at a press briefing during the 2014 Annual Meeting of the American Society of Clinical Oncology, Dr. Hinrichs explained that new therapies are needed for metastatic cervical cancer, because chemotherapy is not curative and rarely provides durable palliation.
“Cervical cancer harbors attractive targets for immunotherapy for the HPV E6 and E7 oncoproteins, but clinical trials in immunotherapy for this disease have been disappointing at this time,” he said.
Adoptive T-cell therapy is an emerging and promising immunotherapy platform, Dr. Hinrichs explained, but its study in epithelial cancers has really been limited, and it has not been studied in cervical therapy.
Objective and Durable Responses
Dr. Hinrichs and colleagues evaluated the use of adoptive T-cell therapy in carcinoma of the uterine cervix, a virally induced malignancy that constitutively expresses the HPV E6 and E7 oncoproteins. They conducted a small trial that included 9 patients with metastatic HPV-positive cancers, and treated them with tumor-infiltrating lymphocytes (TIL) selected for HPV-E6 and -E7 reactivity (HPV-TIL).
All patients received a median of 81 x 109 T cells (range, 33 to 159 x 109) as a single infusion, and the infused cells possessed reactivity against high-risk HPV E6 and/or E7 in 6 of 8 patients. There were 2 patients with no HPV reactivity, and they did not respond to treatment.
Treatment with HPV-TIL infusion was preceded by nonmyeloablative conditioning and was followed by high-dose bolus aldesleukin (Proleukin, Chiron Corporation), an interleukin-2-like product.
Of the 6 patients with HPV reactivity, 3 experienced objective tumor responses by RECIST, 1 partial response and 2 complete responses.
One patient with a complete response was a 36-year-old woman with chemotherapy-refractory HPV-16+ squamous cell carcinoma. “She had been treated with 3 different cytotoxic chemotherapy regimens and had multiple tumor sites, and had a complete response and no evidence of disease at 18 months, and her scans at 22 months look the same,” said Dr. Hinrichs.
The other patient who achieved a complete response was also 36 years old and had chemoradiation-refractory HPV-18+ adenocarcinoma. “Her primary tumor was very aggressive, and at the time of surgery, it was found to have spread to the pelvis and distant sites,” he explained. “She had a complete regression, for 15 months now.”
Both patients also demonstrated prolonged repopulation with HPV-reactive T cells following their treatment, and increased frequencies of HPV-specific T cells were detectable after 13 months in 1 patient and 6 months in the other. Conversely, 2 patients with HPV-reactive TIL that did not respond to treatment did not display repopulation with HPV-reactive T cells.
The most common adverse events were hematologic, and the other most common toxicity was related to infection, Dr. Hinrichs pointed out, with about half of patients experiencing febrile neutropenia. None of the patients had infusion reactions, and all of the hematologic events were completely reversible.
“This study offers proof of principle that immunotherapy can induce regression of cervical cancer and that adoptive T-cell therapy can mediate regression of epithelial cancer,” Dr. Hinrichs concluded. “Continued investigation of HPV-TIL for metastatic cervical cancer is warranted.”
He added that they plan to expand the trial to 35 patients and that there is a separate cohort for noncervical HPV-related cancers.
Exciting Despite Small Numbers
Two experts have expressed enthusiasm over these results.
“This is a very hard group to treat, and if the disease recurs, they essentially have zero survival,” commented David O’Malley, MD, gynecologic oncologist and assistant professor, Ohio State University Comprehensive Cancer Center, the Arthur G. James Cancer Hospital, and the Richard J. Solove Research Institute, Columbus. “So anything that offers the possibility of a complete response is very exciting.”
However, these results have to be taken in the context of a very small trial as well as a fairly toxic regimen that is very expensive to initiate, he told Medscape Medical News. “But if these responses are found to be durable, then this is an exciting new avenue to pursue for these women with little to no choices.”
Michael Birrer, MD, PhD, director of medical gynecologic oncology, Gynecologic Oncology Research Program, Massachusetts General Hospital in Boston, agreed that these results were exciting, despite the limited number of patients.
“For metastatic cervical cancer, the prognosis is amazingly dim, with what used to be about a 3.7-month survival now has been extended to about 6 months with bevacizumab [Avastin, Genentech, Inc],” he said. “But it is uniformly fatal. Still, we don’t see complete remissions, and we certainly don’t see prolonged remissions. So despite the small numbers, this is quite provocative and quite interesting.
“On top of that, this is an immune therapy intervention which has been around a long time, but there is a renewed interest in it because of the PD-1 drugs,” Dr. Birrer continued. “But because this is a viral propagated disease with HPV as the target, it all makes sense. Even though the numbers are small, I think a lot of us are quite excited about it.”
This study was supported by the National Cancer Institute, National Institutes of Health. The authors have disclosed no relevant financial relationships.
2014 Annual Meeting of the American Society of Clinical Oncology: Abstract LBA3008. Presented June 3, 2014.
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