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Researchers, oncologists embrace the ‘concept of a cure’
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The decades-long quest for cancer vaccines has yielded FDA approvals for just three types of therapies.
Two of them have reached the market in the past 6 years.
Those recent successes — along with new data presented at the 2012 ASCO Annual Meeting related to vaccine development for several tumor types — have researchers and oncologists optimistic that more big breakthroughs in immunotherapy are on the horizon.
“We have learned a lot about what does not work,” Jedd Wolchok, MD, medical oncologist and director of immunotherapy clinical trials at Memorial Sloan-Kettering Cancer Center, told HemOnc Today. “Now we are taking the next step forward, exploiting what can work.”
Results of preclinical studies and human trials have helped researchers make considerable progress in development of vaccines for breast and pancreatic cancers, Wolchok said.
Jedd Wolchok, MD, medical oncologist and director of immunotherapy clinical trials at Memorial Sloan-Kettering Cancer Center, said recent research breakthroughs necessitated the identification of molecular mechanisms that either activate or constrain immunity.
Source: Photo courtesy of Jedd Wolchok, MD, reprinted with permission.
Both types were spotlighted at ASCO, as was an experimental drug that demonstrated an ability to significantly improve OS among patients with glioblastoma, the deadliest form of brain cancer.
That new data, along with the emergence of ipilimumab (Yervoy, Bristol-Myers Squibb) — a human monoclonal antibody that allows cytotoxic T lymphocytes to recognize and destroy melanoma cells, thereby extending survival — has added to the evidence that the immune system is capable of controlling advanced cancers in humans, said Duane A. Mitchell, MD, PhD, assistant professor of neurosurgery at Duke University and associate director of the Duke Brain Tumor Immunotherapy Program.
“Cancer vaccines do hold the potential for long-term surveillance and suppression of tumor growth,” Mitchell said in an interview. “The concept of a cure is very attractive and promising with this treatment approach. There is a potential for immune-based treatments that is unique in terms of capacity for long-term benefit.”
Smarter strategies
In 1981, the FDA approved the original vaccine to protect against the hepatitis B virus, which can cause liver cancer. It became the first cancer preventive vaccine to be successfully developed and marketed.
In 2006, the agency approved Gardasil (Merck) to prevent HPV types 16 and 18, which are responsible for about 70% of cervical cancer cases. Four years later, the FDA approved sipuleucel-T (Provenge, Dendreon), a first-in-class therapeutic vaccine for men with metastatic prostate cancer.
Elizabeth Ann Mittendorf
“Immunology is still a relatively young field, and over the past 10 to 15 years, the progress that has been made with respect to understanding the immune system and how it works has been remarkable,” Elizabeth Ann Mittendorf, MD, assistant professor in the department of surgical oncology at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “It has allowed us to be much smarter with our strategies.”
Many of those strategies focus on activation and inhibitory checkpoints that control immune response.
Unlike hepatitis or polio, in which disease cells are quickly identified by the immune system as foreign, most of the targets that cancer cells reveal are similar to molecules that are found on healthy cells.
“We have learned how to get the immune system to respond more aggressively against things that it is usually willing to tolerate,” Wolchok said. “That has necessitated the identification of molecular mechanisms that either activate or constrain immunity.”
Appropriate endpoints
When cancer vaccine research was in its infancy, investigators may not have evaluated the most appropriate trial responses, Mitchell said.
In early-stage trials, researchers typically look for tumor shrinkage as evidence that a particular treatment is beneficial.
“In the last decade, in cancer immunotherapy trials, we began looking at OS in patients who have received treatment, despite a lack of evidence of tumor shrinkage,” Mitchell said. “We were appreciating the fact that the patients were living longer, or at least doing better. That would suggest either there may have been a delay in tumor growth or a change in tumor biology that was not recognized as tumor shrinkage.
“Guidelines have been developed and recommendations have been made in terms of how to evaluate responses to immune-based criteria,” she said. “That is a big change.”
Researchers also have improved their selection of patients for clinical trials, becoming more cautious and increasing their chances for success.
Alfred E. Chang
“Traditional research investigations have dealt with patients who have failed conventional therapies and who have advanced diseases,” Alfred E. Chang, MD, chief of surgical oncology in the department of surgery at the University of Michigan Health System, said in an interview. “The efficacy of vaccines to date in advanced-disease populations has been pretty poor.”
Patients with advanced disease have immune systems that are not necessarily intact or strong enough to fight off antigens, and tumors also have ways to elude active vaccine treatments, Chang said.
“Vaccines by themselves will need to be used in combination with other therapies — either conventional modalities, such as chemotherapy and radiation, or other immune adjuvant antibodies that either enhance the immune system or block tumor suppressive mechanisms that come into play,” Chang said.
The combination of immunotherapy and existing treatment modalities may seem counterintuitive. For example, chemotherapy typically depletes immune cells and is thought of as an immunosuppressive.
“Studies have shown that the recovery from chemotherapy can be leveraged to enhance immunologic responses,” Mitchell said. “Chemotherapy may have beneficial effects to stimulating the immune response, such as getting rid of cells that are suppressive to the immune system, providing a larger window for expansion of immune response.”
Brain tumors
Mitchell and colleagues have explored several approaches to enhance immunity against pediatric and adult brain tumors, including cellular immunotherapy. Initially, there were significant questions as to whether the immune system could penetrate the central nervous system.
“Although the normal immune system does not actively survey the central nervous system, once the T cell is activated and alerted that there is a potential pathogen that should be eradicated form the body, those cells circulate all compartments of the body, including the brain,” Mitchell said. “We know the immune system can access the brain and kill tumors within that site. At one time that was a major conceptual limitation.”
Mitchell and colleagues harvest cells from brain tumor patients in the lab and attempt to retrain the immune system to recognize tumor cells more efficiently. Mitchell presents antigens that have been isolated from their tumor cells to the patients’ own immune system.
“We grow large numbers of antigen-presenting cells called dendritic cells,” he said. “They are responsible for stimulating immune response to a variety of viruses, bacteria and tumors. We load these patients’ dendritic cells with genetic material that we have isolated from their own tumors and returned their antigen-loaded dendritic cells back to the patients.”
ImmunoCellular Therapeutics Ltd., a California biotechnology company, presented data at ASCO that showed its experimental drug ICT-107 — an autologous dendritic cell vaccine pulsed with class I peptides from tumor-associated antigens — tripled OS rates among patients with glioblastoma.
Sixteen newly diagnosed patients received the vaccine plus standard care, which included surgery, radiation and chemotherapy.
The results showed the regimen improved 2-year OS (80% vs. 26%), 3-year OS (55% vs. 16%), 4-year OS (50% vs. 12.1%) and 4-year PFS (38% vs. 5.6%) compared with historical patients treated with standard care alone.
The data show there is downregulation of both the tumor-associated antigens that ICT-107 targets, as well as CD-133, a cancer stem cell marker, in some of the patients, Manish Singh, PhD, president and CEO of ImmunoCellular, said in a press release.
A phase 2B, double blind, placebo-controlled trial of ICT-107 is under way at 25 sites, including Massachusetts General Hospital and Dana-Farber Cancer Institute.
“The continued impressive survival data we have seen to date and the timely enrollment in our ongoing phase 2 trial further build our confidence that targeting [cancer stem cell markers] may provide a breakthrough in the treatment of glioblastoma,” Singh said.
Breast cancer
Peptide vaccines have been the subject of extensive research, but early clinical trials that enrolled patients with metastatic disease were fairly unsuccessful, Mittendorf said.
Other trials involve peptide-based vaccines that contain major histocompatibility complex (MHC) class I or II molecules.
Mittendorf and colleagues presented early data at ASCO from a phase 2b trial on an MCH class II peptide vaccine called AE37 (Generex Biotechnology), which is intended for women who have completed treatment for HER-2–positive breast cancer.
“Our group has always thought that a better role for peptide vaccines would be to give them to patients who have been rendered disease-free with our standard-of-care therapies in order to prevent disease recurrence,” Mittendorf said.
After 22 months of follow-up, the vaccine reduced risk of relapse by 43%, according to study results. The recurrence rate was 10.3% among vaccinated patients vs. 18% in controls.
A strong reduction of recurrence was found in patients with lower levels of HER-2, Mittendorf said.
Approximately 25% of breast cancer patients who overexpress HER-2 are currently eligible for treatment with trastuzumab (Herceptin, Roche). Patients who express lower levels of HER-2 are not given this therapy.
“HER-2–derived peptide vaccines work with women with any degree of HER-2 expression,” Mittendorf said. “Patients with lower levels can benefit from these vaccines, too.”
AE37 triggers CD4+ T cells that help the immune system respond to foreign antigens. AE37 takes the native peptide and adds an additional sequence called li-Key hybrid peptide, allowing the peptide to induce a stronger immune response, Mittendorf said.
“If you can teach the immune system to recognize HER-2 as foreign, then if there were any remaining tumor cells circulating in the bloodstream, the T cells would be able to destroy them before they became an established disease,” she said.
Breast cancer survivors are at risk for microscopic circulating tumor cells that could eventually gather and set up host, potentially becoming an area of metastasis in the bone, liver or lung.
AE37 is not a cure-all, but it could be used in conjunction with conventional treatments as an additional therapeutic approach to prevent breast cancer recurrence, Mittendorf said.
“These early results are very promising, suggesting that the AE37 breast cancer vaccine warrants further investigation in a phase 3 trial,” she said.
Use in pancreatic cancer
Patients diagnosed with pancreatic cancer have limited options.
Resection is the only known chance of a cure. Median OS is 4 to 6 months from diagnosis, and the estimated 5-year survival rate is 4%, according to the American Cancer Society.
Jeffrey Hardacre
“Even after a tumor has been removed for pancreas cancer and the patient receives standard adjuvant therapy — chemotherapy or chemotherapy with radiation — expected survival is generally 18 to 24 months,” Jeffrey Hardacre, MD, associate professor of surgery at Case Western University School of Medicine and University Hospitals Seidman Cancer Center, told HemOnc Today. “Telling patients, ‘Even if we get the cancer out, overall survival is maybe 2 years,’ is not good news. We are trying to make those numbers better.”
There have been several variations to the same therapy for pancreatic cancer patients — combining the latest cytotoxic chemotherapies with radiation therapy — without much success, Hardacre said.
In a multi-institutional phase 2 trial, Hardacre and colleagues added the hyperacute immunotherapy algenpantucel-L (NewLink Genetics) to standard adjuvant therapy for 70 patients who successfully underwent pancreatic surgical resection. The median age of the patients was 62 years, and 53% were men.
Algenpantucel-L is an allogeneic pancreatic cancer vaccine based on the concept of hyperacute rejection. It is composed of two human pancreatic ductal adenocarcinoma cell lines that have been genetically engineered to express alpha(1,3)-galactosyl epitopes by using retroviral transfer of the murine alpha(1,3)-galactosyl transferase gene.
These epitopes are responsible for hyperacute rejection. It is theorized that when these cells are given as a vaccine to a patient whose pancreatic cancer has been resected, the patient will recognize the vaccine cells as abnormal, destroy them and, in the process, prime his or her own immune system to help prevent a recurrence of pancreatic cancer.
The primary endpoint was 1-year DFS. Secondary endpoints were OS, toxicity and immunologic analysis.
One-year DFS was 62% compared with historical controls of less than 50%, study results showed. One-year OS was 86% vs. 69% for historical controls.
A subgroup analysis showed patients who received 300 million cells/dose demonstrated improved 1-year DFS (81% vs. 51%; P=.02) and OS (96% vs. 79%; P=.053) compared with those who received 100 million cells/dose.
There were no grade-4 adverse events attributable to the vaccine. Less than 12% of patients experience a grade-3 event related to the vaccine. The most common adverse effects were grade-1/grade-2 injection site reactions.
“Overall, our patients had improved OS out to 3 years compared to historical data,” Hardacre said. “It is just preliminary data, but particularly the DFS and OS data at 1 year were encouraging enough to begin a multicenter, prospective phase 3 trial.”
The phase 3 trial began in 2010 and has a projected enrollment of 720 patients, Hardacre said.
A philosophical evolution
The improved survival demonstrated in recent immunotherapy trials do not indicate that a cure for cancer is within reach. However, it may help trigger a shift in how researchers, clinicians and, ultimately, patients view cancer.
“There are melanoma patients I treated with ipilimumab more than 5 years ago who had scans that looked abnormal, and their scans look just as abnormal today,” Wolchok said. “Are they cured? I don’t know. The scans look abnormal, but they are alive and living their lives despite having this disease that would have been predicted to end their lives many years ago.
“As a human population, we may need to think differently about how we use the word ‘cure,’” Wolchok said. “I try to educate my patients that our goal is to turn this disease from something you die from into something you live with.”
One of the challenges will be to train the immune system not just to eradicate tumors but to provide long-lasting memory against recurrence, Mitchell said.
“In other treatment modalities in which we administer a drug, we know when we stop administering that drug, the therapy modality can no longer exhibit any antitumor benefits,” Mitchell said. “The goal of immune-based treatments is to establish immunologic therapies against tumors like we have against viruses and other pathogens.”
As with any evolving field, however, one new answer invariably leads to several more questions, forcing researchers to identify new roadblocks around which cancer cannot pass. Therein lies the greatest challenge, Mittendorf said.
“Unfortunately, it’s been said that one dumb tumor is smarter than 10 smart oncologists,” she said. – by Anthony Calabro
References:
- NCI Cancer Vaccines Fact Sheet. Available at: cancer.gov/cancertopics/factsheet/therapy/cancer-vaccines. Accessed Aug. 9, 2012.
- The following were presented at the 2012 ASCO Annual Meeting; June 1-5, 2012; Chicago:
- Hale DF. Abstract #625.
- Hardacre JM. Abstract #4049.
- Phuphanich S. Abstract #2087.
Disclosures:
- Wolchok receives research grant support from and is a consultant to Bristol-Myers Squibb. Chang, Hardacre, Mitchell and Mittendorf report no relevant financial disclosures.
Which is the bigger obstacle to cancer vaccine development: clinical challenges or lack of funding?
Basic and clinical research in cancer biology and vaccine development is at the heart of tweaking the immune system for a cure that will wipe out cancer forever.
Pravin T.P. Kaumaya
Many drugs available today to treat cancer have horrific and toxic side effects. Training a cancer patient’s own body immune system to destroy tumors will revolutionize treatment, and great strides are being made to understand the complexity of biological and immunological processes associated with cancer.
One could argue that tumors are akin to viruses and, as such, have developed ways to evade immune intervention. However, the difference is that viruses have evolved to change their coat proteins due to external pressure, whereas cancer cells are pluripotent and are able to divide an unlimited number of times. This results in an ability of cancer cells to develop resistance due to upregulation of different biological pathways by which they proliferate and metastasize.
Cancer is not a single disease. It is a heterogeneous disease, and the idea of a single-agent, magic bullet monoclonal antibody therapy has failed miserably. Combination therapy is the path forward, and we need to cast a wide net with a concerted multi-prong strategy based on an improved understanding of the tumor microenvironment, immunosuppressive factors and multiple signaling pathways.
There is a plethora of hurdles facing combination therapy that need to be overcome, including lack of preclinical animal models, inadequate clinical trials, design and methodologies, lack of immune monitoring strategies and biomarkers for stratification of cancer patients, guidelines for assessment of clinical endpoints and a patient’s depressed immune status. Nevertheless, despite these obstacles, the future of vaccine immunotherapy with improved targeted vaccines/drugs, improved efficacy and lowered toxicity is on the near horizon. Innovative treatments that can restore dysregulated processes by inhibiting signal transduction and compensatory pathways are in the works that could tame the worst of cancers.
Pravin T.P. Kaumaya, PhD, is a professor of obstetrics/gynecology, molecular and cellular biochemistry, and microbiology, director of the division of vaccine development, and director of the Peptide and Protein Engineering Laboratory at The Ohio State University College of Medicine. Disclosure: Kaumaya reports no relevant financial disclosures.
Money will be the bigger obstacle.
Leonard G. Gomella
From a technical standpoint, the progress we made in the last decade can be duplicated. The technology will allow everything to move forward in a much more rapid pace.
The obstacle, of course, is going to be, how do we pay for all of these innovative therapies? The costs of these drugs likely will slow progress.
The classic example is what is currently happening with sipuleucel-T. There was big excitement for the first-in-class drug, but the costs raised a major red flag.
When you look at sipuleucel-T and you cost it out and compare it with medications for hematologic malignancies, advanced breast cancer or gastrointestinal cancers, the difference between the cost of immunotherapy and other cancer therapies is the fact that immunotherapy tends to be all front-loaded.
The high cost happens over a 4- to 6-week period rather than some of the other therapies that can go on for months or even years. One month of sipuleucel-T can cost more than $90,000, but you pay for it and that’s it, vs. paying $4,000 or $5,000 a month for years in some other cases.
The other problem is the fact that companies are not going to be investing millions of dollars in developing a drug if, at the end of the day, no one is going to pay for it. It is uncertain how companies will be incentivized to develop innovative therapies that are costly. That’s where medicine, technology, politics and economics all will collide. Nobody is writing a blank check for these advances anymore.
Leonard G. Gomella, MD, FACS, is the Bernard W. Godwin Professor of Prostate Cancer and chairman of the department of urology at Thomas Jefferson University in Philadelphia. He also is associate director of clinical affairs for the Kimmel Cancer Center at Jefferson. Disclosure: Gomella reports no relevant financial disclosures.
Perspective
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Jill O’Donnell-Tormey, PhD
Cancer vaccination and treatment with other active immunotherapies is just beginning to take off. Yes, the production costs are high right now, and that’s due in part to the high risk involved in developing these complex therapies. But the promise of durable protection against cancer long after treatment — which immunological memory provides — is tantalizing and achievable, and that’s going to be a major attraction for payers. As the science and technology powering this field continue to advance, we’ll see companies identifying likely hits earlier on in the drug development pipeline while weeding out the misses. Better drug candidates going into trials means fewer failed trials, and that will be a major factor in de-risking investment overall, which will help bring cost down. Winners will result in even more durable protective responses than we see today, across more cancer types and among more patient populations. The math changes then over the extended lifespan of a greater number of patients, and the relative cost of three to nine injections of an immunotherapy becomes quite low compared with years of treatment with other therapies. And as immune-based treatments become more efficient and effective, patient demand to be treated with them also will rise, and that will allow manufacturers to lower prices and ease the burden on insurance payers. In the meantime, however, nonprofits can play a key role in pushing science and industry together beyond these initial steps and into a real sprint. The Cancer Research Institute, for example, does this by investing philanthropic dollars in state-of-the-art clinical trials of highly promising experimental therapeutic agents obtained from companies through novel venture capital deals that provide benefits to both the company and to the charity in the event of product success and commercialization. By bringing our nonprofit’s unique scientific expertise to bear on the analysis of a candidate immunotherapy, companies can more rapidly assess the value to patients — and to shareholders — a drug will have, and will be more likely to fast track development of that product, getting life-saving treatments to patients sooner. As a result of this process, the economics of immunotherapy development are likely to improve alongside their effectiveness, and we believe the pace of progress on improving their effectiveness is going to accelerate from here.Click Here to Manage Email Alerts