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Opinion: Translational Research in Crisis

Turning discoveries made in academic labs into innovative therapies requires a radically new approach.

By | September 10, 2013

FLICKR, _TAWCANAcademic research in the United States faces two chronic problems: an inability to become financially self-sufficient, and inefficient partnerships between academia and industry. Without solving both of these problems, an increase in federal funding alone will not suffice.

Translational research is meant to bridge the gap between basic research and the clinic in order to facilitate the transition of knowledge and discovery into therapeutics. However, because of our current approach to translational research, there is still significant discordance between preclinical findings and clinical results. Such discordance has hindered the clinical impact of academic research, despite sizeable investments made in it.

This trend is no longer viable. It’s time to break away from the status quo and reinvent translational research. Doing so could enable therapeutic breakthroughs and drive up return on investment, which in turn would facilitate additional funding for academic research.

Preclinical problems

Preclinical studies are being conducted based on some problematic principals. That most experimental animals are inbred and housed in aseptic conditions might account for some differences seen between preclinical findings and clinical outcomes. Using outbred animals kept in more natural conditions could generate results that better recapitulate those seen in clinical settings.

Immunological studies investigating cancer treatments are usually performed in healthy animals transplanted with tumors. Once the immune response rejects the tumor, follow-up studies to determine whether it might relapse are not typically conducted. In humans, tumors develop spontaneously, and recurrence is a major issue. Thus, transgenic animals that develop cancer spontaneously are more suitable for testing cancer vaccines or other immunotherapeutic strategies. Follow-up studies should also be performed to determine whether the tumor returns after a therapeutic appears to be initially successful.

Xenogeneic animal models are often used as theoretical test tubes to determine the efficacy of drugs or immunotherapies. Results derived from xenogeneic models, which are immune-deficient to allow engraftment of human tumor cells, don’t always carry over into clinical studies because they focus on a single factor while ignoring the involvement of complex genes and endogenous elements in immune-competent hosts. While preclinical models used to date have generated useful data in basic research, particularly where understanding the mechanism of function of certain molecules is important, translational research requires new approaches.

Clinical issues

The reliability of clinical trial findings is determined by statistical significance when comparing treatments with controls. For instance, if a therapeutic approach works in one out of 20 patients, it would be considered statistically insignificant because of the variations within the test group, and the drug’s development may be abandoned. Alternatively, researchers may re-test the therapy in larger cohorts of patients to see if it might reach statistical significance. If a treatment does reach statistical significance in larger cohorts of patients, the drug could potentially be approved, even though a considerable fraction of patients did not respond to it. Today, patients are often stratified into treatment and control groups based on animal studies, which as stated, often fail to mimic the outbred nature of humans. This approach has hindered publication of novel findings and the development of personalized medicine where individual variations are appreciated during the trials and interpretations of the results.

When a treatment works even in one patient, it would still be significant given that humans respond to treatments differently. Rather than testing the idea in a larger group, we should determine why a specific treatment works in some patients and failed in others so as to establish eligibility criteria for further trials.

Herceptin was initially approved only for breast cancer patients with HER-2/neu-positive tumors. Similarly, the National Cancer Institute’s Steven Rosenberg and his colleagues have shown the success of adoptive cell therapy in some but not all melanoma patients, greatly reducing its potential for Food and Drug Administration approval. And cancer vaccines, which have shown to be successful in preventive settings during preclinical studies, have largely been abandoned because of their failure to treat advanced cancers.

It’s puzzling to think we would ignore a preventive cancer vaccine that could potentially prevent tumor relapse because it can’t be used to treat advanced diseases. Vaccines against infectious diseases are also successful in preventive but not therapeutic settings, yet we expect unreasonably more from cancer vaccines.

The way forward                                                                                                               

While a boost in funding alone won’t cure translational research, strategic investments will be needed to change the current system. Federal agencies such as the National Institutes of Health (NIH), the National Science Foundation, and the Department of Defense should focus on supporting projects that address the aforementioned preclinical and clinical challenges. Though some recent NIH requests for applications address provocative questions, none have yet challenged the current translational approach.

Now is the time for change. Let’s start by setting up new standards for translational research. In doing so, we can signal a turning point in the history of medical research. Otherwise, academic research will continue to suffer because the US economy can no longer afford to support it.

Masoud H. Manjili is an associate professor of microbiology and immunology at the Virginia Commonwealth University School of Medicine and Massey Cancer Center, where his research focus is on cancer and immune response.

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September 10, 2013

The Cancer Research Institute, a non-profit organization dedicated to funding laboratory and clinical studies aimed at harnessing the cancer-fighting power of the immune system, has been the leader in cancer immunotherapy for 60 years. Having helped to establish the field of cancer immunology, which is now on a firm scientific footing and gaining momentum, CRI is placing an increasing emphasis on the translation and clinical application of scientific discovery and identifying innovative ways to help bring the most promising immunotherapies to more cancer patients sooner.

Masoud Manjili in his September 10 Opinion: Translational Research in Crisis rightfully asserts that academic research faces significant problems turning laboratory discovery into innovative therapy. He further notes that there is “…significant discordance between preclinical findings and clinical results” and “…inefficient partnerships between academia and industry,” two challenges that must be addressed if academic research is to yield maximum clinical benefit and attain the ultimate goal of saving patients’ lives.

The Cancer Research Institute has tackled these two challenges with its two newest research programs, the Clinical Laboratory Integration Program (CLIP) and its Clinical Accelerator. The Clinical Accelerator is a unique venture philanthropy program that enables unprecedented research collaboration between biopharmaceutical companies and a network of leading academic clinicians and scientists. Along with our collaborator in this program, Ludwig Cancer Research, we work to identify promising new drug combinations, partner with companies to gain access to these drugs, and then provide investment capital and clinical trial support to the academic investigators to help kick-start clinical development. The program demands global collaboration among researchers in academia and industry, facilitates partnered clinical development by disparate biopharma companies, utilizes a one-of-a-kind clinical infrastructure that took over a decade to assemble, and invests in research-driven (as opposed to product-driven) clinical trials.

CLIP is CRI’s translation research program, but it importantly provides a two-way street between the clinic and the lab. A primary objective of the program is to start at the clinic, analyzing patient samples from clinical trials testing novel cancer immunotherapies and correlating these results with clinical outcomes.  In this way, in-depth immunological monitoring, genetic and proteomic analyses, and biomarker discovery from patient samples guides further laboratory investigation, where mechanistic studies can be designed and animal modeling performed. The basic discoveries emanating from this type of research can then inform the design of future clinical trials and ultimately improve the development of cancer immunotherapies, as well as our ability to target the patients who will have the best chance of benefiting from a particular treatment.

Utilizing new paradigms to guide strategic investments in translational and clinical research can lead to better outcomes for patients. New models championed by not-for-profits like the Cancer Research Institute can lead the way towards a systemic change in funding structures that more efficiently capitalize on the phenomenal discoveries taking place in both the lab and the clinic.

Avatar of: Paul Stein

Paul Stein

Posts: 124

September 10, 2013

I'm not so sure the author understands the preclinical issues very well.  I attribute that to his field of cancer and the immune response and the selected species that are used almost exclusively.  It's not inbred versus outbred, but microanimals versus real ones as models.  (Hint:  dogs.)  Until that issue is tackled, translation will continue to be stuck in the mud, and no amount of money will help.

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