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Old 03-31-2015, 01:31 AM
gdpawel gdpawel is offline
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Default Cancer Immunotherapy 'Has Entered Mainstream'

Cancer immunotherapy takes centre stage in a series of articles about harnessing the immune system for therapy published March 25 as a special issue of Science Translational Medicine.

While the articles trace the progress being made across all fields of medicine, it is in cancer that immunotherapy has made the greatest strides.

"Recent treatment successes with antibodies that regulate immune activation have essentially ended the debate about whether the immune system sees and regulates cancer growth. Tumor immunotherapy has entered the mainstream and is a strategy to be considered within the clinician's toolbox of standard therapies for cancer," write Alexander M. Lesokhin, MD, from Memorial Sloan Kettering Cancer Center in New York City, and colleagues in a perspective.

"The recent approvals of two drugs that block the function of the immune checkpoint programmed cell death 1 (PD-1) have firmly planted tumor immunotherapy in the mainstream of clinical oncology," they write.

The two PD-1 inhibitor drugs that have reached the market — nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck & Co) — have been both approved for use in melanoma, and nivolumab was recently approved also for use in non-small cell lung cancer. But there are numerous clinical trials in progress in many other cancer types and with other compounds, and these PD inhibitor drugs "are expected to be approved in multiple malignancies," the authors write.

Dr Lesokhin and colleagues also trace the development of the first immune checkpoint inhibitor, ipilimumab (Yervoy, Bristol-Myers Squibb), now approved as a first-line treatment for melanoma. This drug acts at a different point in the immune cascade, as a CTLA-4 blocker, and another agent with this mechanism of action, tremelimumab (Pfizer) is in ongoing clinical trials.

"Perhaps the most clinically exciting observation has been the remarkable durability of responses with CTLA-4 blockade. Although responses are restricted to a minority of treated patients, those who respond are likely to enjoy a durable response, often measured in years," they comment.

Both the PD-1 inhibitors and the CTLA-4 blockers were discovered as a result of basic research directed at a better understanding of the immune system, notes a related editorial authored by Jeffrey Bluestone, PhD, and Qizhi Tang, PhD, both from the University of California, San Francisco.

Cancer immunotherapy has shown signs of a "decisive victory over certain cancers," they write, but "the path to this remarkable victory began in a seemingly unrelated quest to understand the molecular basis of immune activation, which revealed myriad T-cell receptor (TCR) subunits and TCR costimulatory and coinhibitory molecules."

"This intricate system of checks and balances is hijacked by cancer cells to evade immune rejection and, in reverse, is defective in autoinflammatory diseases that lead to the disruption of normal tissue functions. This deeper mechanistic understanding of the human immune system drove the discovery of a plethora of new drugs," they write.

Dr Lesokhin and colleagues predict that further therapeutic advances will result from this work. "The multiple molecules involved in T-cell costimulation raise hopes that more patients will ultimately derive benefit from continued basic research and clinical study of this family of therapeutic targets," they write.

"All of this is enough to make one wonder if perhaps there is a limit to the reign of the 'Emperor of All Maladies'," they conclude, in a reference to the sobriquet for cancer in the title of the Pulitzer Prize–winning book by Siddhartha Mukherjee.

Adoptive Cellular Therapy

Another success story in harnessing the immune system to treat cancer — the adoptive cellular therapy approach — is discussed in a perspective article authored by Carl June, MD, from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and colleagues.

This group were pioneers in the development of chimeric antigen receptor (CAR) engineered T-cells for the treatment of leukemia, and they have now teamed up with Novartis to commercialize this therapy, which is developed individually for each patient. Other groups are also developing this CAR T-cell approach, including a team at the National Cancer Institute that is collaborating with Kite Pharmaceuticals. Results from early clinical trials show durable responses and suggest that this CAR T-cell approach can "eradicate disease" and have generated great excitement among the hematological malignancy community.

In their article, Dr June and colleagues say that the "remarkable success in patients treated on trials at academic centers has enticed unprecedented interest from the biotechnology and pharmaceutical industry."

"The recent entry of the pharmaceutical industry to this area has dramatically changed the prospects for the widespread availability of engineered T-cells," they write, adding that this approach is now rapidly advancing toward approval by the US Food and Drug Administration.

"The field faces numerous scientific, regulatory, and economic obstacles and challenges in educating clinicians in the use of ACT," they write. "Surmounting these obstacles will require collaboration between academia and biotechnology in order to ensure that therapy with engineered T-cells is established as a viable approach for common human malignancies."

Sci Transl Med. 2015;7:280ed3, 280sr1, 280ps7.

Citation: Cancer Immunotherapy 'Has Entered Mainstream'. Medscape. Mar 25, 2015.
Gregory D. Pawelski
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Old 11-10-2015, 08:09 AM
gdpawel gdpawel is offline
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Default Study Identifies New Opportunities for Targeted Immunotherapy

A team of NCI researchers has reported that several types of gastrointestinal cancers have tumor-specific mutations that can be recognized by the immune system, potentially offering a new therapeutic opportunity for patients with these tumors.

In the study, published October 29 in Science, researchers showed that T lymphocytes (cell-killing white blood cells) targeting tumor-specific genetic mutations can be identified in metastatic gastrointestinal tumors, according to the study’s senior author, Steve Rosenberg, M.D., chief of the Surgery Branch in NCI’s Center for Cancer Research.

The finding is important, Dr. Rosenberg said, because the most common form of immunotherapy, checkpoint inhibition, hasn’t shown efficacy against most gastrointestinal cancers.

But this new study, he continued, “opens the door” to the development of a different type of immunotherapy, called adoptive cell transfer, for these and possibly many other cancers.

Single Patient Prompted Study

Some cancers, such as melanoma and smoking-induced lung cancer, have many genetic mutations, making them particularly immunogenic—that is, they tend to elicit very strong immune responses.

Checkpoint inhibitors, such as nivolumab (Opdivo) and pembrolizumab (Keytruda) have shown the most effectiveness against these types of cancer.

But, Dr. Rosenberg said, it’s been unclear whether common epithelial cancers, including gastrointestinal cancers, which tend to have far fewer mutations than melanoma and lung cancer, induce a tumor-specific immune response.

Last year his research team reported that T cells directed against a unique mutation in the tumor of a woman with advanced cholangiocarcinoma (bile duct cancer) were identified in lung metastases. The patient then underwent adoptive cell transfer, using an expanded pool of her own mutation-specific T cells, and experienced regression of her metastatic lung and liver tumors that is ongoing for more than 2 years.

The new study, which builds on that finding, included nine additional patients being treated at NCI as part of an ongoing clinical trial. The patients all had metastatic cancer, including colorectal, pancreatic, bile duct, and esophageal cancer. The analysis also included data from the patient with cholangiocarcinoma.

More Patients and More Possibilities

Overall, the patients’ tumors had a modest number of genetic mutations. Even so, the researchers were able to identify T cells that recognized at least one tumor-specific mutation in metastatic tumors in 9 of the 10 evaluated patients. The NCI team has since expanded this effort, identifying mutation-specific immune cells in 15 of 16 patients studied, Dr. Rosenberg said.

In several patients, the research team isolated immune cells that recognized a mutation in the KRAS gene that is commonly seen in patients with pancreatic and colorectal cancers and many other cancers. The KRAS mutation was the only mutation recognized by the immune system seen in more than one patient’s metastases.

Given the general frequency of the KRAS mutation in some cancers, the finding lays the groundwork for a possible “off-the-shelf” immunotherapy treatment—T cells engineered to express a receptor that recognizes tumors with this mutation, Dr. Rosenberg noted.

Two other patients from the original group of 10 were additionally treated with their own mutation-specific T cells but did not respond to treatment. In these patients, the researchers found, few if any infused T cells remained in the patients’ circulation for a prolonged period. In the patient with cholangiocarcinoma, however, at one month after treatment, nearly a quarter of her circulating T cells were the mutation-specific adoptively transferred cells.

A Blueprint for Many Cancers

There is still much research to be done, Dr. Rosenberg said, including how to improve the persistence of the transferred T cells. But he is optimistic about what this finding could represent.

“The whole idea of identifying mutations in a patient’s cancer and identifying and engineering T cells that specifically recognize those mutations is a blueprint for treating many different types of cancer,” he said.

The NCI team is already moving ahead with plans for an early phase clinical trial that follows on these findings, Dr. Rosenberg said.

Source: National Cancer Insitute
Gregory D. Pawelski
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Old 11-29-2015, 06:31 PM
gdpawel gdpawel is offline
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Default Biomarkers in Oncology

Robert A. Nagourney, M.D.

The treatment of advanced human malignancies has progressed slowly since the first introduction of systemic chemotherapy in the 1950’s. Our capacity to harness adaptive immunity using T-cell checkpoint inhibitors has added a new modality for treatment. It has long been recognized that the selection of candidates for treatment using biological markers could enhance outcomes, facilitate drug discovery, reduce costs and curtail futile care. These predictive/prognostic biological markers are known as “biomarkers”.

Biomarkers are defined as “objectively measured indicators of biological processes or response to a therapeutic intervention.[1] The FDA uses four subgroups I) exploration, 2) demonstration, 3) characterization and 4) surrogacy, with only surrogacy accepted for drug approval. Recognized surrogates include serum cholesterol, HIV viral load and blood pressure. Biomarker validation including calibration, precision, specificity and sensitivity remains the principal developmental hurdle. In this expanding era of immunotherapy, the need for validated predictive biomarkers has rapidly grown.

Checkpoint inhibitors targeting PD1, PDL1and CTLA4 offer fertile ground for discovery. PDL1 (CD279) is highly expressed in T, B, NK-cells and macrophages and serves as a receptor for PDL1, PDL2, B7H3, and B7H4. PDL1 expression in tumor cells, immune cells or both has been proposed as a predictive biomarker yet technical variability, differing cutoffs (1%, 5%, 10%, 50%), frozen vs FFPE and varying clinical circumstances continue to complicate treatment-candidate selection. Recently, BIM expression was reported as a new PD1 response biomarker.[2] Additional markers, including CD8+/CD20+ ratios, circulating cytokines and the use of tumor exomes are under investigation.[3] Anti-CTLA4 (ipilumab) has also been the subject of biomarker analyses with response shown to correlate with T-cell count, T-cell activation, inflammatory micro-environment and T-cell clonotypes. Whole exome sequencing has been used to screen candidate neo-antigens with immune signatures then shown to correlate with outcome (p=0.01).[4] However, these investigators noted, “no gene was universally mutated”.

The complexity of human immunity continues to challenge those seeking to identify specific mutations, splice variants or amplifications that can segregate responders from non-responders The NEJM study used phenotypic autologous T-cell response to identify relevant neo-antigens while the Mayo investigators defined a “response phenotype” using BIM expression Thus genotypic interrogation can be enhanced through the study of the human phenotype. Closing the gap between genotype and phenotype offers unique opportunities to advance cancer therapy and drug development.

To date, genomic prediction of clinical response to “molecularly targeted agents” has met with limited success. One study provided a 1.5% (1/68) objective response rate in colon cancer patients who received molecularly targeted therapy,[5] similar to the 4% (1/27) response rate observed in BRAF mutation (+) colon cancer patients selected for Vemurafenib.[6] A recent trial that randomized patients to “molecular selection” vs. “physician choice” showed no difference in time to progression (2.3 vs 2.0 months) with the authors concluding that “Off label use of molecularly targeted agents should be discouraged”.[7]

The decades-long focus upon altered cell proliferation over more modern concepts of altered cell survival (apoptosis), a focus upon the cancer cell and not its micro-environment and the promotion of genomics over functional platforms have contributed to slow progress in cancer research. Nonetheless, the application of laboratory models capable of interrogating the biologic basis of clinical response at the phenotypic level has the potential to inform and accelerate future developments.

We have explored functional analyses that examine human tumor biology phenotypically. The Ex Vivo Analysis of Programmed Cell Death (EVA-PCD) incorporates the modern tenets of drug induced programmed cell death in the context of human tumor primary culture microspheroids that recapitulate native state human tumors replete with stroma, vasculature, inflammatory cells, cytokines, and cell-cell interactions. Results have been shown to correlate with response, time to progression and survival and have been the subject of prior meta-analyses.[8],[9] Preliminary work supports their capacity to examine biologic response modifiers like VEGF inhibitors.[10] More recently this platform has been applied to the study of human ovarian carcinoma using cell death measures as correlates with metabolomic endpoints.[11]

We are witness to a growing appreciation of human tumor phenotypic analyses as important adjuncts to genomic, transcriptomic and proteomic platforms. Phenotypic analyses have the capacity to interrogate the complexities, redundancies and promiscuities of human tumor biology. The intelligent combination of phenotypic (functional) and analyte-based (molecular) platforms will facilitate patient selection and drug discovery.

[1] Firestein GS. A biomarker by any other name. Nature Clinical Practice Rheum Vol 2:12; 635, 2006

[2] Dronca RS, et al. BIM as a predictive T cell biomarker for response to anti-PD-1 therapy in metastatic melanoma Proc Int’l Canc Immunotherapy Conf, Ab A007, 2015

[3] Whiteside Theresa. Immune responses to cancer: are they potential biomarkers of prognosis? Frontiers in Oncology 3:107;1-8, May 2013

[4] Snyder A, et al. Genetic Basis for Clinical Response to CTLA4 blockade in melanoma. NEJM 371:2189-2199, 2014

[5] Dienstmann R, et al. Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials.Molecular Cancer Therapeutics, 11(9)2062-2071, 2012

[6] Hyman David M., Puzanov Igor, Subbiah Vivek, et al. (2015) Vemurafenib in multiple nonmelanoma cancers with BRAF V600 Mutations. NEJM 373;8:726-736

[7] LeTournea Christophe, Delord Jean-Pierre, Goncalves Anthony, et al. (2015) Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicenter, open-label, proof-of-concept, randomized, controlled phase 2 trial. Lancet, 16-13;1324-1334

[8] Bosanquet Andrew G, Kasper Gertjan J, Larsson Rolf, et al. (2007) Individualized Tumor Response (ITR) Profiling for Drug Selection in Tailored Therapy: Meta-analysis of 1929 Cases of Leukemia and Lymphoma. Blood 110; abs 3471

[9] Apfel Christian, Souza Kimberly, Cyrill Hornuss, et al. (2013) Accuracy and clinical utility of in vitro cytometric profiling to personalize chemotherapy: Preliminary findings of a systematic review and meta-analysis. J Clin Oncol 31, 2013 (suppl; abs e22188)

[10] Weisenthal LM et al Cell Culture detection of microvascular cell death in clinical specimens of human neopalsms and peripheral blood. J Intern Med. 264 (3) 275-287, 2008

[11] D’Amora Paulo, Dale Ismael, Salzgeber Marcia, et al. A Phase II study in epithelial ovarian cancer (EOC) to correlate drug sensitivity and metabolomic signatures with objective response (OR), time to progression (TTP) and overall survival (OS). 19 Congresso Brasileiro de Oncologia Clinica, Oct 2015.
Gregory D. Pawelski
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Old 09-06-2017, 07:06 AM
gdpawel gdpawel is offline
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Default Progress of Cancer Immunotherapy: The Tip of the Iceberg

Cancer Care, and Research News
By Dana-Farber Cancer Institute

If the human immune system was a powerful racing car, you could say that scientists in the past few years have gained unprecedented control over how to make it accelerate, and what causes it to slow or stop. This knowledge has spawned new immunotherapy drugs that are delivering dramatic benefits to some patients with advanced cancers.

“Checkpoint blockers are transformational,” asserts Laurie H. Glimcher, MD, president and CEO of Dana-Farber and a prominent immunologist, referring to drugs that disable the brakes that cancer cells use to fend off an attack on them by immune system T cells.

“The idea that you can take someone who has stage IV metastatic cancer and halt the cancer – and manage it more like a chronic disease…it’s remarkable,” Glimcher says.

“However,” she adds, “it’s just the tip of the iceberg.” Beyond the impressive but limited successes of recent immunotherapy advances lies the potential to bring the strategy to more patients and more kinds of cancer.

The iceberg’s tip also represents current knowledge of the powerful immune system’s intricate and complex set of controls. Much of what will be needed to shape and steer the immune attack against cancers remains to be discovered.

“There’s so much we don’t understand,” Glimcher says. “Our task is to figure out the answer to at least two questions. First, why do only some patients with tumors that can respond to immunotherapy – like melanoma, lung, bladder and kidney – not respond to immunotherapy? Why is it only 20 or 30 or 40 percent? Why don’t all of them respond?

“And second, why do some cancers not respond at all, like pancreatic, prostate, ovarian, and breast cancer, glioblastoma, and colon cancer other than patients with Lynch syndrome?”

Despite those unanswered questions, the science behind immunotherapy is far more advanced than it was even a decade ago. For nearly 100 years, since the idea first emerged, efforts to harness the immune defenses as a cancer treatment met with many failures and limited success – even though the immune system, which evolved mainly to combat infectious viruses and bacteria, is capable of eliminating body cells that have become cancerous. Many strategies focused on stimulating the immune response with vaccines or removing T cells from a patient, “educating” them in the laboratory, and returning them to the body to seek out and destroy cancer cells. But except in a few instances, these measures didn’t spark an effective immune reaction.

It took what Glimcher calls an “Aha!” insight to jump-start the field of cancer immunotherapy.

That realization was that the best way to activate the immune system was not by stepping on the gas pedal – but by removing the brakes. Scientists learned that cancer cells evade the immune forces by activating molecular “checkpoints” that both conceal the identity of the cancer cells and switch off the immune response. These natural checkpoints are crucial to health – without them, people would be much more vulnerable to misguided attacks on normal tissue, as in autoimmune diseases like lupus. The role of one of those checkpoints on cancer cells, PDL-1, was identified by Dana-Farber’s Gordon Freeman, PhD, who in 2000 discovered that it partnered with another molecule on T cells, PD-1, to stave off attack by immune T cells. Another checkpoint, CTLA-4, also switches off the immune response.

“The T cells can get exhausted, and go into a state where the tumor is masked from the immune system, or the tumor secretes substances that create a highly immunosuppressive microenvironment” around the tumor, like a moat around a castle, says Glimcher.

The “moat,” a microenvironmental barrier that prevents killer T cells from invading the tumor, is composed of many kinds of suppressor cells including macrophages, dendritic cells, endothelial cells, and others. Glimcher’s own research has identified key molecular signaling pathways in the tumor microenvironment that are hijacked by cancer cells as protection; she and others are exploring strategies for “reprogramming” the environment to boost the immune response against tumors.

The discoveries of checkpoints that allow cancer to escape immune attack rapidly led to the development of “checkpoint blockade” antibody drugs that free T cells to attack and kill cancer cells. Dana-Farber’s F. Stephen Hodi, MD, director of the Center for Immuno-Oncology, led a groundbreaking clinical trial showing that ipilimumab (Yervoy), which blocks CTLA-4, could slow advanced melanoma in a significant number of patients and prolong their survival. Several other antibody drugs that block the PD-1/PD-L1 interaction have been approved, including pembrolizumab (Keytruda), nivolumab (Opdivo), and atezolizumab (Tecentriq). These drugs have found a place in treating non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin lymphoma, and are being tested in other forms of cancer.

While many other checkpoint blockers are in company pipelines or clinical trials, researchers are exploiting the power of the immune system in other ways.

One approach that has gotten a lot of attention because of some early dramatic successes is CAR T cells. The patient’s T cells are removed and genetically modified in the laboratory to produce special receptors on their surface that recognize a specific protein on tumor cells. Then billions of the CAR T cells are infused into the patient to seek out and destroy the cancer. In some patients with very advanced blood cancers this strategy has had remarkable success, but it also can produce severe side effects that need to be closely managed.

Cancer vaccines continue to intrigue immunologists. Even though there are effective vaccines against the human papilloma virus (HPV), which causes cervical cancer, and some head and neck and anal cancers, only a minority of people at risk have undergone vaccination, Glimcher says. “It’s really a crime,” she says. “No women should die of cervical cancer.” She says she believes effective vaccines for non-viral cancers are possible, but the field is still in its infancy. Such vaccines would provoke the immune system to react against proteins displayed on the surface of cancer cells.

“Ultimately,” says Glimcher, “I think the answer is going to be combination therapy, just as it was for HIV/AIDS. The key to turning HIV from a lethal disease to a chronic disease was realizing you have to attack it with several drugs at the same time. It’s going to be trying to figure out which drugs work in which patients, precision immuno-oncology both for the tumor and the immune system.”

The potential of immuno-oncology is just beginning to be realized. Uncovering more of the iceberg will take both a much more detailed understanding of how the immune response is controlled and the tools or treatments to manipulate it for clinical benefit.

“I can’t think of a place that’s better equipped than Dana-Farber to take this on,” Glimcher reflects. “We have fantastic researchers who work closely with clinicians. And we can actually generate drugs here – we can take a basic discovery in the lab, do a proof of principle assay in animals, identify tool compounds, and then our chemists can turn that into a drug that could go into humans. Very few institutions have this capability.”

Source: Dana-Farber’s 2017 issue of Paths of Progress
Gregory D. Pawelski
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