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Researchers Use Immunotherapies To Combat Cervical Cancer, Melanoma.

Several major media sources report on research presented at the American Society of Clinical Oncology conference on immune therapies for different cancers. For instance, two of last night’s national news broadcasts discussed one of these studies, with both showing The National Cancer Institute’s Dr. Christian Hinrichs. Many of the articles, including those from USA Today, the New York Times, and the Wall Street Journal, discuss multiple studies presented at the ASCO conference.

NBC Nightly News (6/2, story 5, 2:25, Curry, 7.86M) reported, “In medical news tonight a ground-breaking development in the fight against cancer. It involves one of the newest approaches, using a patient’s own immune system to attack the disease and researchers now report its worked for the first time against cervical cancer.” Dr. Hinrichs, study lead, was shown saying “The goal of it is to completely eliminate the cancer and have it never come back.” Dr. Hinrichs added, “This is building on new knowledge how the immune system works. We now have several approaches that are showing these dramatic results.”

The CBS Evening News (6/2, story 8, 0:20, Dubois, 5.08M) showed Dr. Hinrichs saying, “The treatment that we do completely rearranges the immune system.” He added, “The idea is to give a single treatment and have the cells wipe out the tumor the same way that they would clear an infection.”

USA Today (6/2, Weintraub, 5.82M) reports that the researchers used “adoptive T cell therapy,” which “helps combat the virus that causes cervical cancer.” With this therapy, physicians “harvest immune cells that are naturally fighting a patient’s cancer, expand them in the lab, and then put them back in the body – essentially enlarging the immune system’s anti-tumor army.” This is “‘the ultimate in personalized therapy. You’re creating a new drug for every patient,’ said Steven Rosenberg, chief of the surgery branch of the National Cancer Institute, who has been working on these therapies since the late 1980s.”

On its website, NBC News (6/3, 7.5M) reports that Hinrichs said, “These are not genetically engineered or genetically modified T-cells,” but are instead “naturally occurring T-cells that were present in the tumor.” However, “in those who do have them, it could represent a lifelong cure, says Dr. Richard Schilsky, chief medical officer for the American Society for Clinical Oncology.” Dr. Schilsky said, “Not all patients respond, but if they do respond, their responses are very long-lasting because the immune system has a memory.” He added, “This is a huge change.”

The AP (6/3, Marchione) reports that “the cervical cancer experiment was the first time an immune therapy has worked so dramatically against a cancer caused by a virus – HPV.” During the “pilot study by the National Cancer Institute, the tumors of two out of nine women completely disappeared and those women remain cancer-free more than a year later.”

HealthDay (6/3, Preidt, 5K) reports that in an “ASCO news release, expert oncologist Dr. Don Dizon” said, “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.”

Meanwhile, Bloomberg News (6/3, Langreth, 2.76M) reports that in one study of melanoma patients, “79 percent of an initial group of 53 patients who received the experimental medicine nivolumab combined with Yervoy [ipilimumab] were still alive after two years, a better result than is seen with existing drugs for advanced melanoma.” Meanwhile, “in another study of 411 advanced melanoma patients who” received an experimental medication “called MK-3475, 62 percent were alive 18 months after starting treatment.”

AFP (6/3) reports on those studies and also reports on another study presented at the ASCO conference in which researchers found that patients given ipilimumab “saw a 25 percent reduced risk of the cancer coming back when compared to a placebo.” The research “involved 951 patients with stage III melanoma, many of whom faced a likely recurrence of cancer since it had spread to their lymph nodes.” The investigators found that “three years after treatment, the survival rate was 46.5 percent in the ipilimumab group and 34.8 percent in the placebo group.”

Reuters (6/3, Beasley) reports that research presented at the ASCO meeting also suggests that an immunotherapy called pembrolizumab may benefit patients with melanoma and certain patients with lung cancer or head and neck cancer.

The Houston Chronicle (6/3, 2.23M) reports that physicians at the ASCO “conference reported success against lung, head and neck, bladder and kidney cancer using immunotherapy, until recently considered a lost cause but now generating great excitement.” Altogether, “more than 70 studies” were presented “this weekend and Monday about the therapy, which drew attention the last two years mostly for melanoma.”

The Wall Street Journal (6/3, Subscription Publication, 5.51M) reports that some of the research has led some oncologists to believe that immunotherapies could ultimately be beneficial for patients with lung, bladder, and kidney cancers, in addition to melanoma.

The New York Times (6/3, Pollack, Subscription Publication, 9.65M) reports, however, that “some experts note that there was initially huge excitement about so-called targeted therapies and about drugs that block the flow of blood to tumors.” Although “those approaches have made a difference, they have not been the panaceas enthusiasts envisioned, and that is likely to be the case with immunotherapy as well.” The Times adds, “‘With anything, all that glitters is not gold,’ said Dr. Richard Pazdur, who as chief of the cancer division at the F.D.A. has a unique insight into how drugs are performing.” Also covering the cervical cancer study are The Hill (6/3, Viebeck, 237K), Medscape (6/3, Nelson, 192K), and MedPage Today (6/3, Smith, 205K). Also reporting on melanoma studies are Reuters (6/3, Berkrot), HealthDay (6/3, 5K), and Medscape (6/3, Mulcahy, 192K).

Investigational Autologous Immunotherapy May Be Beneficial For Patients With mRCC.


Renal and Urology News (6/3, Charnow, 46K)reports that research presented at the American Society of Clinical Oncologyannual meeting indicated that “an investigational autologous immunotherapy”known as AGS-003, “used in combination with sunitinib significantly improved
long-term survival in patients with unfavorable-risk metastatic renal cellcarcinoma (mRCC).” During “a phase 2 study of 21 subjects who received the dualregimen, investigators...observed a doubling of the expected medianprogression-free survival (PFS) and overall survival (OS), with 52% of patientssurviving more than 30 months and 23% surviving for more than 5 years.”



Unprecedented Survival Seen With Melanoma Combination

The combination immunotherapy of ipilimumab (Yervoy, Bristol-Myers Squibb) and the investigational antibody nivolumab (Bristol-Myers Squibb) continues to rewrite the melanoma record book.

Concurrent use of the 2 immune-checkpoint blockade agents has produced the "unprecedented" overall survival rates for metastatic melanoma of 85% at 1 year and 79% at 2 years in a phase1 study, said lead author Mario Sznol, MD, from the Yale University School of Medicine in New Haven, Connecticut.

He discussed the data during a press conference here at the 2014 Annual Meeting of the American Society of Clinical Oncology® (ASCO).

That's amazing.

The median overall survival for the 53 patients treated in the study was 40 months — also unprecedented. "That's amazing," Dr. Sznol told Medscape Medical News.

The best median overall survival in a cohort of patients with metastatic melanoma, even those treated with new targeted therapies, had been about 24 months, he said.

"The advance here is more than incremental," he emphasized. "This is why oncologists are so excited."

Combination therapy is the future of treatment for melanoma, said Ryan Sullivan, MD, from the Massachusetts General Hospital Cancer Center in Boston, who was not involved in the study.

"We are already using combinations for the BRAF-targeted treatment of metastatic disease," he told Medscape Medical News. The combination of the MEK inhibitor trametinib (Mekinist, GlaxoSmithKline) and the BRAF inhibitor dabrafenib (Tafinlar, GlaxoSmithKline) was approved by the US Food and Drug Administration for advanced melanoma earlier this year.

This new study demonstrates where we are going with immunotherapy.

"This new study demonstrates where we are going with immunotherapy," Dr. Sullivan noted.

However, the most effective immunotherapy combination (or combinations) remains to be seen, Dr. Sullivan said. Impressive efficacy data are emerging for other programmed death1 (PD-1) agents, such as MK-3475 (Merck), and other experimental combination therapies are in early-phase trials.

Another expert was more cautious. "This is a small group of patients," said Patrick O'Day, MD, from the University of Southern California Keck School of Medicine in Los Angeles, who moderated the press conference.

Dr. O'Day pointed out that the overall response rate for the combination does not appear to be much different from the PD-1 single agents reported thus far. Furthermore, the combination had more toxicity than either ipilimumab or nivolumab used as single agents.

Complete Response Rates Likely Higher Than Reported

All 53 patients enrolled in the phase1 study, which is ongoing, had inoperable stageIII or IV (metastatic) melanoma and had received up to 3 previous therapies.

The group received nivolumab and ipilimumab every 3 weeks for 4 doses (12 weeks), followed by nivolumab every 3 weeks for 4 doses. Then, at week24, concurrent combination treatment was administered every 3 months.

Last year at ASCO, Dr. Sznol reported that the concurrent ipilimumab and nivolumab combination yielded an objective response rate of 40%.

But the rate was 53% in the subset of 17 patients who received a combination that contained maximum doses — also a new high in the treatment of metastatic melanoma.

This year, Dr. Sznol was back with an update on response rates and survival. The 53 patients have about another year of follow-up.

The confirmed complete response rate is now 17% (9 of 53 patients), which is up from the 10% (5 of 52 patients) reported last year. Dr. Sznol said that the complete response rate is "probably higher," but was tamped down by CT scans that show tremendous amounts of detail.

To illustrate that partial responses are often very substantial, Dr. Sznol revealed that tumor reduction of at least 80% was observed in 22 of 53 patients (42%). "Many of those had near complete responses," he said.

There has been concern in the field that patients with BRAF genetic mutations, which are present in about half of all melanomas, might not respond as well to immunotherapy, Dr. Sznol explained.

But activity was similar in patients with mutant and wild-type BRAF disease. Likewise, activity was similar regardless of programmed death ligand1 (PD-L1) status, which is an emerging biomarker in melanoma and other cancers.

Trial Approved For Immunotherapy Medicines To Treat Glioblastomas.


Reuters (6/1, Steenhuysen) reported that the National Cancer Institute has given approval to US researchers to design a trial for two immunotherapy treatments for treating patients newly diagnosed with glioblastomas. Bristol-Myers Squibb Co. makes the medicine Yervoy (ipilimumab) and an experimental medicine called nivolumab. Dr. Mark Gilbert, a brain tumor researcher at University of Texas MD Anderson Cancer Center in Houston, disclosed the news at the American Society of Clinical Oncology meeting in Chicago.

Dendritic Cell Vaccine Has Positive Effect On PFS In Patients With Glioblastoma.


The Cancer Network (6/2, Lawrence) reports that “a phase II trial evaluating the use of a dendritic cell vaccine, ICT-107, has shown that the immunotherapy had a positive effect on progression-free survival in patients with glioblastoma.” But, the research, presented at the American Society of Clinical Oncology meeting, “failed to meet its primary endpoint of overall survival.”

Addition Of Lenalidomide To Rituximab/chemotherapy May Be Effective In Elderly Patients With Newly Diagnosed DLBCL.

Medscape (5/31, Harrison, 192K) reported that research published in the Lancet Oncology suggests that “the addition of lenalidomide (Revlimid) to a standard rituximab/chemotherapy combination is impressively effective in elderly patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), and does not add to toxicity.” For the study, “49 elderly patients were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin and vincristine), and half were randomly assigned to also receive lenalidomide.” Investigators found that “adding the immunomodulatory agent increased the overall response rate to 92%.”

T-cell Changes: Why Only Some Respond to Ipilimumab

The immunotherapy ipilimumab (Yervoy, Bristol-Myers Squibb Company) works amazingly well in some patients, hardly at all in others. A groundbreaking study that used deep sequencing techniques offers some clues as to why.

Ipilimumab, which is marketed for melanoma but is being explored in several other cancer types, including prostate cancer, acts as a checkpoint blocker by inhibiting cytotoxic T lymphocyte– associated antigen–4 (CTLA-4).

Immune repertoire sequencing has confirmed that blocking CTLA-4 increased turnover and diversity of the T-cell repertoire in some patients with advanced prostate cancer or metastatic melanoma, but also showed that patients who survived longest maintained clones of high-frequency T-cells they had developed before starting treatment.

The new finding was reported by Lawrence Fong, MD, professor in residence, Division of Hematology/Oncology, University of California, San Francisco, and colleagues in Science Translational Medicine.

"We demonstrated how anti-CTLA-4 changes the T-cell clones circulating in a patient," Dr. Fong told Medscape Medical News. "This 'scrambling of the deck' could allow a patient to generate T cells that target the cancer and could explain why this treatment takes time to work. This is consistent with what people suspected might be going on, but our results are the first demonstration of this."

"The surprising finding was that better clinical outcomes were associated with maintenance of a preexisting immune response," Dr. Fong added.

Monitoring changes in the T-cell repertoire might eventually help clinicians meet 2 of the challenges of treating cancer with targeted biological agents: selecting patients who are likely to benefit from treatment (while avoiding unnecessary expense and toxicity risk for patients unlikely to benefit), and avoiding premature discontinuation of treatment in patients with delayed responses.

For example, only around 10% to 15% of patients with malignant melanoma respond to ipilimumab, but long-term data reported in 2013 showed that 17% to 25% of responders survived more than 3 to 10 years, vs average survival of 10 to 11 months in similar patients treated with conventional chemotherapy.

T-cell clonotype monitoring, as described by Dr. Fong and colleagues, might help physicians select the subgroup of patients most likely to respond to anti-CTLA-4 treatment. However, Dr. Fong said that the deep sequencing techniques used in this study are less likely to be useful in initial patient selection than in monitoring response after beginning treatment.

CTLA-4 is a T-cell surface protein that acts as a brake on killing of tumor cells. Anti-CTLA-4 antibodies block the brake and allow T cells to attack and kill cancer cells. Dr. Fong's group examined the underlying mechanism by using the LymphoSIGHT (Sequenta, Inc.) immune repertoire sequencing platform to measure the frequency of individual, rearranged T-cell receptor β (TCRβ) genes as a way of characterizing the diversity of rearrangements, known as T-cell clonotypes.

The study was done using cryopreserved peripheral blood mononuclear cells (PBMCs) from 25 castration-resistant prostate cancer (CRPC) patients concurrently enrolled in a phase 1/2 clinical trial of ipilimumab (up to 4 doses ranging from 1.5 to 10 mg/kg and GM-CSF 250 µg/kg/day), and from from 21 patients concurrently enrolled in a phase 1 trial of single-agent tremelimumab (a CTLA-4 blocker that had been under development by Pfizer) at 15 mg/kg given every 3 months. The clonotype repertoires and survival times in these 2 groups of cancer patients were compared with those of a cohort of 9 untreated control participants, which had been obtained from Cellular Technology Limited.

This study showed in that in the CRPC patients treated with ipilumumab and GM-CSF and in the metastatic melanoma patients treated with tremelimumab, the immunotherapy treatment increased TCR diversity (seen in the number of unique TCR clonotypes) and that the clonotype repertoire continued to evolve during months of treatment. However, the number of clonotypes that increased with treatment did not have a straightforward association with clinical outcome. Instead, improved overall survival was seen in patients who maintained high-frequency clones that they had at baseline, prior to treatment. Patients who had decreases in their baseline highest-frequency clonotypes also had shorter survival.

The important clonotypes associated with better survival included T cells with high-avidity T-cell receptors, such as virus-reactive T cells. The authors speculate that these clones might represent preexisting high-avidity T cells.

"We propose that for most long-term survivors, high-avidity clones present at baseline are readily available after checkpoint inhibition to recognize relevant tumor antigens and mediate durable responses. For others, an increasingly diverse and evolving TCR repertoire allows for discovery and expansion of subdominant tumor-reactive clones. Because only a proportion of patients obtain long-term benefit, identification of these preferential clonotypes could improve patient selection for patients receiving single-agent CTLA-4 blocking antibodies," the authors wrote.

The researchers also suggested that determining antigen specificity for persistent clonotypes could inform potential vaccination strategies in combination or in sequence with CTLA-4 blockade to increase efficacy in the majority of patients who will not benefit from CTLA-4 blockade alone.

Dr. Fong told Medscape Medical News that the study data did not align neatly with either the "threshold" model of CTLA-4 blockade or the "attenuation" model, but suggested that preexisting T-cell responses might hold the key to better outcomes after anti-CTLA-4 blockade.

Dr. Fong said that patients appear to develop individual-specific immune responses to their own tumors rather than responses to shared antigens. "I think we showed that people do not neatly conform to a model based on animal models. If anything, we see both models in action: an increase in the diversity of the repertoire (threshold model), but a maintenance of the high-avidity T cells (attenuation model)," he commented.


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