Tag Archives: cancer

Defeating Leukemia: A smile that says “Thank the mice”

Posted on December 12, 2012 by | 1 Comment

A couple of days ago the New York times published a heart warming story about a young girl named Emma Whitehead whose acute lymphoblastic leukemia – which had previously defied all therapies – has gone into full remission following treatment with a novel gene therapy that programmed her immune system to target the cancer cells. The New York Times report noted that the therapy used a vector based on the HIV-1 virus to deliver genes – known as a chimeric antigen complex (CAR) – to modify  Emma’s T-cells so that they would destroy the leukemia cells.  This isn’t the first example of how scientists are using the properties of this deadly virus to develop powerful new therapies, back in 2009 we discussed how such a lentiviral vector was used to treat the genetic disease cerebral X-linked adrenoleukodystrophy. Emma wasn’t the only patient to benefit from this therapy developed by scientists at the University of Pennsylvania, 9 other patients with intractable leukemia have experienced partial or full remissions.

Emma2

Earlier today I received an e-mail from a long-time reader of this blog asking:

Did I dream there was an SR post on this already?”

Well my friend, you were not dreaming.

Last year we published a post entitled “A breakthrough against Chronic Lymphocytic Leukemia…thank the mice!” which discussed the role of animal research in the development of this therapy, and in particular that of mice the evaluation of chimeric antigen complexes in order to identify a complex that would induce a long-lasting immune response against the cancer cells. Our post also linked to an article on the Weizmann Wave Blog entitled “Cancer Breakthrough 20 Years in the Making” which described the basic biomedical research – mice were again crucial – that underpinned this field.

At the time I concluded the post by saying:

So there you have it, behind the headlines are years of graft by hard-working and innovative scientists, who utilised a wide range of experimental approaches – among which animal studies figure prominently – to develop a novel therapy for CLL.”

And I say the same again today. At a time when funding of medical research in the US is facing the threat of very damaging cuts, Emma’s story is a reminder of why you should write to your Senator and Congressional Representative today!

Paul Browne

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Hope for young cancer victims as stem cell transplantation restores functioning sperm in monkeys.

Posted on November 2, 2012 by | 2 Comments

Chemotherapy plays a crucial role in treating many cancers, but unfortunately some chemotherapy has a side effect of destroying the spermatogonial stem cells that are responsible for producing sperm.  Adult men who need to undergo chemotherapy have the option of cryopreserving their sperm in order to give themselves the option of having children in the future, but for young cancer patients who have not yet gone through puberty this is not an option.

Today the BBC news reports on a major advance; scientists at the University of Pittsburgh and Magee-Womens Research Institute have announced that they had taken samples of the spermatogonial  stem cells from 12 adult and 5 prepubescent male macaques and cryopreserved them, administered the macaques with a chemotherapy course that eliminated the remaining spermatogonial stem cells (SSCs), and then thawed and implanted the preserved stem cells after the course of chemotherapy had ended. Nine out of 12 adult monkeys and three out of five prepubescent monkeys were later able to produce sperm again, and additional studies showed that these sperm were capable of fertilising eggs. They were able to show that the sperm were produced by transplanted SSCs and not stem cells that had survived chemotherapy by labelling the transplanted cells with a harmless virus that expressed a Green Fluorescent Protein tag (another interesting application of this Nobel Prize winning technology).

Macaque monkeys play a crucial role in this and many other fields of medical research. Image courtesy of Understanding Animal Research/Wellcome Images

The study by Dr Kyle Orwig and colleagues, published on Thursday in Cell Stem Cell (1), publish work builds on almost 20 years of research, and they discuss how studies in mice and rats initially demonstrating the feasibility of SSC transplantation, while follow-up studies in a range of large animals (including pigs, sheep and monkeys) provided further support for the approach.

The feasibility of this approach is supported by observations in lower animal models that SSCs from donors of all ages, newborn to adult, can regenerate spermatogenesis (Shinohara et al., 2001; Ryu et al., 2003) and that SSCs can be cryopreserved and retain spermatogenic function upon thawing and transplantation (Dobrinski et al., 1999, 2000; Brinster, 2002).

Large animal models are critical for examining the safety and feasibility of experimental therapies before they are translated to the clinic. SSC transplantation has been reported in seven previous large animal studies (Table S1 available online). All of those studies, except for one in the boar (Mikkola et al., 2006), employed irradiation to destroy spermatogenesis and cause infertility. There is a dearth of information on the efficacy of SSC transplantation in chemotherapy-treated large animals, probably due to the significant challenges associated with clinical management of animals treated systemically with highdose chemotherapies that cause severe hematopoietic deficits (Hermann et al., 2007). However, the importance of this experimental paradigm should not be overlooked because high-dose alkylating chemotherapies are used routinely for conditioning prior to hematopoietic stem cell (HSC) transplantation and are associated with high risk of infertility (Wallace et al., 2005”

This study added to this previous research by demonstrating for the first time that it is possible for cryopreserved SSCs to generate functioning sperm in a primate following high dose chemotherapy, and is a major step forward in this field.

Experts in reproductive science have welcomed this study, with Professor Allan Pacey on the University of Sheffield saying:

This report is a very useful step forward and clearly shows that the science of spermatogonial stem cells transplantation might one day work for humans. And, although the authors report relatively low efficiency so far, in the context of someone who does not have any banked sperm to fall back on, these odds are probably very encouraging to make this kind of approach worthwhile.”

It’s certainly true that further research in macaques is needed to ensure that the sperm that result from this technique give rise to healthy offspring, and that cancer cells are not inadvertently transplanted with the SSCs. The second potential problem is already being addressed by Dr. Orwig’s team, who last year demonstrated that where there is a risk that SSCs may be contaminated with cancer cells, it is possible to screen to remove the cancer cells before transplantation. It is also worth noting that such autologous hematopoietic stem cell transfer using cells isolated from a patient’s own bone marrow is a standard part of therapy for some cancers such as lymphoma, and in this week’s paper Dr. Orwig and colleagues highlight the role of animal research in developing this therapy (for which Joseph Murray and Donnall Thomas shared the 1990 Nobel Prize in Physiology or Medicine):

Adult stem cell transplantation for homologous tissue regeneration was first described for primates in the 1950s when bone marrow stem cells were used to reconstitute the hematopoietic systems of monkeys and humans treated with chemotherapy or radiation (Crouch and Overman, 1957; Thomas et al.,1957). Large animals, primarily the dog and monkey, were instrumental for establishing the safety, feasibility, and range of applications for bone marrow transplantation. Today, approximately 50,000 bone marrow or HSC transplant procedures are performed worldwide each year for diseases ranging from cancer to thalassemia, sickle cell anemia, and autoimmune and immune-deficiency disorders (Appelbaum, 2007; Powellet al., 2009).”

Such history is very encouraging, but it is worth paying attention to the final paragraph of the this week’s Cell Stem Cell paper, which notes the great potential of the technique, stresses the need for further development and evaluation, and points out that even when animal studies have played their part further development and study in human trials will be required to realise the full potential of the SSC transfer:

Several promising techniques are in the research pipeline (i.e., SSC transplantation,testicular tissue grafting or xenografting,and in vitro development of gametes) that may allow patients receiving gonadotoxic therapies to preserve their future fertility (Brinster, 2007; Rodriguez-Sosa and Dobrinski, 2009; Sato et al., 2011). SSC transplantation has the unique potential to regenerate spermatogenesis in the autologous environment of the seminiferous tubules, enabling the recipient male to father his own genetic children, possibly through normal coitus. As with hematopoiesis, large animal models that are relevant to human anatomy and physiology will be important for translating the SSC transplantation technique to the human fertility clinic. Considering the successful regeneration of spermatogenesis in the nonhuman primate model reported here and the fact that patients are already preserving testicular tissue and/or cells, clinical translation of the SSC transplantation technique appears imminent. Responsible development of the technology in a clinically relevant nonhuman primate system will help to address issues of safety and feasibility. As with hematopoiesis, the clinical significance and breadth of applications for SSC transplantation will ultimately be established in human patients.”

Dr. Orwig and his colleagues at University of Pittsburgh and Magee-Womens Research Institute for a study that will bring hope to many thousands of cancer patients, and we congratulate them on it, but they also deserve a pat on the back for an excellent paper that shows their appreciation for the long-view of medical research.

1)      Brian P. Hermann, Meena Sukhwani, Felicity Winkler, Julia N. Pascarella, Karen A. Peters, Yi Sheng, Hanna Valli, Mario Rodriguez, Mohamed Ezzelarab, Gina Dargo, Kim Peterson, Keith Masterson, Cathy Ramsey, Thea Ward, Maura Lienesch, Angie Volk, David K. Cooper, Angus W. Thomson, Joseph E. Kiss, Maria Cecilia T. Penedo, Gerald P. Schatten, Shoukhrat Mitalipov, Kyle E. Orwig “Spermatogonial Stem Cell Transplantation into Rhesus Testes Regenerates Spermatogenesis Producing Functional Sperm” Cell Stem Cell – Vol. 11, Issue 5, pp. 715-726 (2012)

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ERV blogs on GMO Herpes vs severe cancer pain

Posted on September 18, 2012 by | 3 Comments

As gene therapy emerges as one of the hottest areas of medical research, one thing that is striking is how it employs viruses – sometimes very nasty viruses - to deliver the gene to where it is needed in the human body.

Yesterday virologist Abbie Smith discussed another excellent example of this on the ERV blog in a post entitled “GMO Herpes vs. severs cancer pain”, describing how scientists at the Universities of Michigen and Pittsburgh have used a genetically modified herpes virus to deliver the preproenkephalin gene – which produced a precursor to pain-killing opiates – to the nerve cells of terminal cancer patients who were suffering from severe pain.

Abbie remarks that “This was one of the most depressing, yet hopeful, papers I have ever read.”. It’s difficult to disagree, after all most of the patients participating in the trial died within 3 months of it starting. But to focus on this sobering statistic would miss the reason for this study, namely that the pain-relief available to patients with severe chronic pain is often inadequate, as the drugs are not specific enough and cause unacceptable side effects when used at the high doses often required for prolonged periods of time. By targeting the opiate molecules to the nerve ccells themselves these side effects can be avoided, and more effective pain relief provided.

The paper “Gene Therapy for Pain: Results of a Phase I Clinical Trial” is available for anyone to read in PubMed Central and makes it very clear that this is a therapy that was discovered, evaluated and refined in animal models of different types of pain before entering this first clinical trial. The first two paragraphs of the introduction noting that:

A significant limitation to the development of analgesic drugs is that off-target effects at doses below the maximal analgesic threshold restrict the ability to selectively interrupt nociceptive neurotransmission1. To address this limitation, we developed a series of replication defective HSV-based vectors to deliver gene expression cassettes directly to DRG neurons from skin inoculation 2, 3. The anatomically defined projection of DRG axons allows targeting of specific ganglia by injection into selected dermatomes. In preclinical studies, the release of anti-nociceptive peptides or inhibitory neurotransmitters in spinal dorsal horn from the central terminals of transduced DRG neurons effectively reduced pain-related behaviors in rodent models of inflammatory pain, neuropathic pain, and pain caused by cancer4-9.

The human PENK gene encodes for preproenkephalin, a precursor protein proteolytically cleaved to produce the endogenous opioid peptides met- and leu-enkephalin. In the spinal cord, enkephalin peptides inhibit pain signaling through actions at presynaptic opioid receptors located on central terminals of primary afferent nociceptors and postsynaptic opioid receptors on second order neurons involved in nociceptive neurotransmission10. HSV vectors expressing opioid peptides appear to be particularly effective in animal models of inflammatory and cancer pain4, 5, 8.”

And in the conclusion:

In preclinical animal studies, skin inoculation of HSV vectors expressing PENK reduce acute hyperalgesic responses27, and reduce pain-related behaviors in models of arthritis28, formalin injection4, peripheral nerve damage6 and bone cancer5. Because this was the first human trial employing HSV vectors to achieve gene transfer, we elected to carry out the phase 1 clinical trial for safety and dose-finding in patients with pain caused by cancer…This Phase I clinical trial primarily addressed the question of whether intradermal delivery of NP2 to skin would prove to be safe and well tolerated by subjects. The small number of patients and the absence of placebo controls warrant circumspect interpretation of the secondary outcome measures. But the observation that subjects in the low dose cohort had little change in the NRS or SF-MPQ while subjects in the higher dose cohorts reported substantial reduction in NRS and improvement in SF-MPQ is encouraging.”

Encouraging is possibly an understatement, seeing clear evidence of therapeutic benefits in a Phase I trial like this is very promising, or as Abbie puts it “A trial turning out this successful is a great starting point for optimizing this kind of therapy.”.

Paul Browne

p.s. Those interested in a more detailed account of the research that led to this clinical trial can find it in this review published in 2008 and available to read online for free.

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Cancer Stem Cells: Mouse studies lead to paradigm shift in cancer research

Posted on August 2, 2012 by | Leave a comment

For the past 15 years one of the most intriguing ideas in cancer research has been that the growth and spread of most – if not all – cancers is driven by cancer stem cells. The hypothesis is that only a tiny proportion of cancer cells, cancer stem cells, have the stem cell-like ability to proliferate indefinitely to produce cells that can differentiate into other cancer cell types. It suggests that the reason why cancer often returns after apparently being eradicated is that while the therapy (surgery/radiation/chemotherapy) may remove the differentiated cancer cells it fails to remove all the cancer stem cells, whose subsequent proliferation results in the cancer’s return.

Multicolored intestine tissue in genetically modified mice allows scientists to track which cells give rise to tumors.
Credit: A. G. Schepers et al., Science (2012) DOI: 10.1126/science.1224676

Today 3 teams of scientists have announced important results that provide the strongest evidence to date that cancer stem cells are indeed at the heart of cancer proliferation.

The first evidence that only a small minority of cancer cells may have the ability to proliferate indefinitely came from a study of leukemia cells in 1997, when Dr Dominique Bonnet and Dr John Dick, then both working at the University of Toronto, observed that when they injected a variety of acute myeloid leukemia (AML) cell populations obtained from human biopsy into immunodeficient mice and analyzed which cells gave rise to leukemia cells in the mice, and found that regardless of the characteristics of injected AML cells the cells that initiated the leukemic cell populations in the mice always expressed the cell surface marker CD34 and lacked the cell surface marker CD38, a key characteristic of stem cells.

Since then similar observations have been made for a wide variety of cancer types, and scientists have discovered important new facts about cancer stem cells, for example in 2009 we discussed how scientists at Stanford University had used genetic modification of bone marrow stem cells to show that leukemia stem cells were very similar to embryonic stem cells.  However, these studies all involved the transplantation of cancer cells into mice, and there has always been some concern that the manipulation of these cells during their isolation from humans and sorting into specific populations before injection into mice may have affected their behavior.

Today, three independent studies of mouse models of brain, skin and intestinal tumours, led respectively by Dr Luis Parada at the University of Texas Southwestern Medical Center, Dr Benjamin Simmons of the Gurdon Institute and Dr Cédric Blanpain of the Free University of Brussels, and Dr Hans Clevers of the Hubrecht Institute, and published in the prestigious scientific journals Nature and Science,  provide the first evidence that cancer stem cells do arise during tumour formation in intact organs, and drive tumour formation.

What these studies all share is that they were able to do this because rather than injecting cancer cells into the mice they used genetically modified mice in which cancer develops spontaneously. Using additional genetic modification to label certain types of cells they were able to track the different cell types involved in the growth and spread of cancer, and even assess the differing effects of standard cancer therapies and therapies that included drugs that specifically target cancer stem cells.

There is an excellent discussion of the three projects and their implications for cancer research in Nature News, and Science Now also offers a informative prespective on the work.  From its very first paragraphthe Nature News article highlights how these studies provide crucial information that could not be obtained through other methods:

Cancer researchers can sequence tumour cells’ genomes, scan them for strange gene activity, profile their contents for telltale proteins and study their growth in laboratory dishes. What they have not been able to do is track errant cells doing what is more relevant to patients: forming tumours. Now three groups studying tumours in mice have done exactly that. Their results support the ideas that a small subset of cells drives tumour growth and that curing cancer may require those cells to be eliminated.”

Commenting in an article in the LA Times, Dr. Owen Witte of the UCLA Broad Stem Cell Center was clear about what these results mean for cancer research.

People can stop arguing…Now they can say, ‘OK, the cells are here. We now need to know how to treat them.’ ”

And “how to treat them” will not be an easy problem to solve, perhaps drugs that target the cancer stem cells or prevent their development may be the answer, but as the Nature News, Science Now and LA Times articles stress we don’t yet know enough about the origins of cancer stem cells to be sure which approach will work.

What is true is that thanks to advanced animal research methods a huge gap in our knowledge of how cancer develops and spreads – a gap that we only recently realised existed – has been filled. As research accelerates to turn this new knowledge into effective cancer therapies we can be certain of one thing; animal research will continue to provide key insights that turn hypothesis into cures.

Paul Browne

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So, what can a growing fly teach us about skin cancer?

Posted on June 13, 2012 by | Leave a comment

Back in April we welcomed launch of the Golden Goose Awards , an annual prize awarded to honor federally funded research  “whose work may once have been viewed as unusual, odd, or obscure, but has produced important discoveries benefiting society in significant ways.”.

The Golden Goose award was developed in response to attacks on basic research by politicians who fail to appreciate the value of basic research, and it is not difficult to imagine that a research project begun back in the 1980’s which sought to determine the role of a gene named “hedgehog” during embryonic development in fruit flies would have been greeted with derision by the usual suspects .

D. melanogaster, an organism whose small size belies its huge contribution to medical science. Image courtesy of André Karwath.

Any such derision would have been badly misplaced. An article posted last week on the Cancer Research UK Science Update blog reveals how studying the hedgehog gene in the fly Drosophila melanogaster ultimately led to the development ofVismodegib, a drug recently approved for the treatment of advanced basal-cell carcinoma by the FDA, noting that:

 For us, the hedgehog’s tale is a testament to the beauty and potential of basic biology. It’s certainly not the first time that our basic research has helped set the stage for a new drug that can help cancer patients, and – given the progress we’re continuing to make in our research centres across the country – we doubt it will be the last.”

I encourage you to read the full CRUK Science Update Blog post “High-impact science: Hedgehogs, flies and skin cancer – the story of vismodegib” , it’s an excellent example of how research on flies, rodents and a range of other organisms combined with studies of cancer genetics in humans to enabled the development of an innovative therapy.

Paul Browne

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The end of cancer? A personal view.

Posted on December 15, 2011 by | 1 Comment

My husband died of stage 4 metastatic esophageal cancer on August 19, 2011.

I have been an advocate for biomedical research, specifically involving animals, for decades. I go to work each and every day supporting researchers involved with discovering new cures or treatments. I dedicate time outside of those duties to promote education regarding the use of animals in such research. I want people to be able to make up their own minds free of rhetoric and sound bites empty of any real information. Research is part of who I am.

All of this became intensely personal for me, more so than it was, in February of 2010 when my husband was diagnosed. They did not need to explain to me how serious his diagnosis was. I already knew. I knew it was going to be a tough battle but he was a fighter. He was not ready to leave me or his daughters or the life we built. Not now. Not to cancer. No way.

He remained a fighter until his very last day on this earth. In our last conversation he told me cancer had only taken his body but he was still free and he will be waiting for me when the time comes for me to shed my body too. I still work in the same hospital where all his treatments had taken place and I eat at the same cafeteria where I bought all his food when he was in the hospital. I still see some of his caregivers in the hallways and they always ask me how I am. They are very caring people and I am sure each and every one of them would applaud an end to cancer. I know I would. I am pretty sure everyone that has been touched by this horrible disease would love to see an end to it, just as I am sure people were very happy to see an end to polio or small pox.

On Monday, author Sharon Begley published an article in The Daily Beast entitled “Could This Be The End Of Cancer?”outlining some of the new developments in the fight against cancer, particularly using vaccines. It is detailed but easy to read, and it was nice to see more information on some of the treatments my husband received. Research for cancer and many other diseases go on each and every day by thousands of people. Some of those people remember what life was like before the current vaccines we take for granted were widely used. In reading the evaluation results for the polio vaccine, you can see how many children were affected and see pictures of them in iron lungs. My generation has never known a friend confined to one of those thanks to those who continued the research that lead to the vaccine. The mortality rates for small pox were up to 35% and yet according to the WHO this disease was eradicated in 1979, thanks to those who developed the first vaccine. I doubt anyone who was born after 1975 could really tell you what small pox looked like without looking it up thanks to those who continued to search and refine the current vaccine.

Immunotherapy – developed through animal research – offers new hope to patients with Chronic Lymphocytic Leukemia, and is an example of recent advances in cancer treatment discussed by Sharon Bagley

Without research, both with animals and humans, or those dedicated to searching for answers, no cures are possible. Will we see vaccines for all cancers in the next 30 years? No one can answer that, just like no one can give you a date when the human race will finally stop wars. But does that mean we should stop looking? Stop striving? Stop hoping for a cure? Absolutely not. Polio and small pox are simple diseases if compared with the complexity of cancer. It is going to take lots of time, lots of man hours and a lot of dedication from a lot of people to finally put this monstrous disease in the “eradicated” file.

It is also going to take a lot of money. On Ms. Begley’s article page is a comment regarding this money. The poster states:

This is a nice read, but … this will never happen. At least not in our life time as Cancer has become a big business. I am a ovarian 3 cancer survivor and I can tell you that there would be a lot of people out of work if there ever was a cure. The Government would fail. “

Do you suppose she is happy about the treatments she received for her disease that has extended her life? Would she reject a vaccine in favor of current treatments if her cancer was to reappear? Somehow I think she would take the easier treatment.

Is finding cures and treatments expensive? You bet it is. Is funding from the government and charities vital to this research? Absolutely. Without it we would not be able to hire the scientists, the biologists, the doctors or the nurses who work tirelessly each and every day, not only to find a cure, but to make every day in the life of a cancer patient the best it can be. And believe me, we are not a rich bunch. We shop at dollar stores and check the clearance section too just like so many people do in our current economic state.

However…

Do you think any one of us would give up their job to find that cure tomorrow? I know I would. In a heartbeat. It is too late to save my husband. But if I could save everyone else, every kid, mother, father, wife, husband and friend, from having to go through what I just went through, I would collect my last paycheck today. Right now.

But until that cure happens, we are going to come to work and continue searching, perfecting, refining and aiming for that day to come. And it will come.

Pamela Bass

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A breakthrough against Chronic Lymphocytic Leukemia…thank the mice!

Posted on September 13, 2011 by | 4 Comments

A challenge that science communicators frequently face when discussing the process whereby a scientific discovery eventually leads to a medical breakthrough is the time that this often takes, indeed by the time that the reports of exciting clinical trial outcomes start to appear in the press the role of the scientists who made the initial discoveries is often relegated to a passing comment…if it is mentioned at all. An example of this comes from the Weizmann Wave blog, produced by the Weizmann Institute of Science.

You may remember reports last month on the very promising results of a small clinical trial where a new immunotherapy technique was used to eradicate cancer cells in patients with Chronic Lymphocytic Leukemia (CLL), a blood cancer for which currently available treatments are often inadequate.  That trial, conducted by scientists at the University of Pennsylvania led by Professor Carl June, involved removing T-cells from the patient, treating the cells with a lentiviral vector that encodes for a Chimeric Antigen Receptor which recognises a protein named CD19 that is found on B-cells, including the cancer cells responsible for CLL, and then infusing the transformed T-cells back into the patients.  As the reported in the Los Angeles Times the results were dramatic, within a few weeks of the infusion the modified T-cells expanded rapidly and targeted the cancer cells in all three paients, so that a year later two of the three patients were still in complete remission.

It’s exciting stuff but as the Weizmann Wave reports the Press Release issued by Penn Medicine noted that this was a “cancer treatment breakthrough 20 years in the making” but “didn’t, however, explain those “20 years in the making.””. The Weizmann Wave goes on to discuss the pioneering basic scientific research undertaken by Professor Zelig Eshhar at theWeizman Institute of Science in the late 1980’s, which you can read about here.

Of course between the basic research undertaken by Prof. Eshhar and his colleagues in the 1980’s and the clinical trial whose outcome was announced last month there was a lot of work to be done. It would be impractical to describe all the different discoveries that made this immunotherapy possible, but one discovery in particular highlights the importance of animal research to this breakthrough.

There have been previous attempts to use Chimeric Antigen Receptors to target T-cells to attack cancer, but these had disappointing results in clinical trials.  A major improvement made by the University of Pennsylvania team was to include an additional motif – named the CD137 co-stimulatory molecule- which greatly enhances the cancer killing ability of the infused T-cells.  In a recent paper published in the Journal of Cancer the University of Pennsylvania team point out that the decision to include CD137 (called 4-1BB in mice) in their Chimeric Antigen Receptor construct was based on promising results in studies undertaken in mice:

 Our group has tested a CAR directed against CD19 linked to the CD137 (4-1BB) co-stimulatory molecule signaling domain to enhance activation and signaling after recognition of CD19. By inclusion of the 4-1BB signaling domain, in vitro tumor cell killing, and in-vivo anti-tumor activity and persistence of CART-19 cells in a murine xenograft model of human ALL (acute lymphocytic leukemia) is greatly enhanced”

Indeed, in a paper published by Professor June and colleagues in the journal Molecular Therapy in 2009 they describe this work in much more detail, highlighting just how groundbreaking the results were:

Previous in vitro studies have characterized the incorporation of CD137 domains into CARs.10,11,29 Our results represent the first in vivo characterization of these CARs and uncover several important advantages of CARs that express CD137 that were not revealed by the previous in vitro studies. We demonstrated that CARs expressing the CD137 signaling domain could survive for at least 6 months in mice bearing tumor xenografts. This may have significant implications for immunosurveillance, as well as for tumor eradication. For example, in a mouse prostate cancer xenograft model, survival of CAR+ T cells for at least a week was required for tumor eradication.30

Long-term survival of the CARs did not require administration of exogenous cytokines, and these results significantly extend the duration of survival of human T cells expressing CARs shown in previous studies.17,31 To our knowledge, this is the first report demonstrating elimination of primary leukemia xenografts in a preclinical model using CAR+ T cells. Furthermore, complete eradication was achieved in some animals in the absence of further in vivo therapy, including prior chemotherapy or subsequent cytokine support.

The long-term control of well-established tumors by immunotherapy has rarely been reported. Most preclinical models in a therapeutic setting have tested tumors that have been implanted for a week or less before initiation of therapy.32 After establishing leukemia 2–3 weeks before T cell transfer, we found that many animals had long-term control of leukemia for at least 6 months. The efficacy of targeted, adoptive immunotherapy in this xenograft model of primary human ALL compares favorably to our prior experience testing the antileukemic efficacy of single cytotoxic (ref. 27 and data not shown) or targeted agents,26 where we have observed extension of survival but not cure of disease. Additionally, we have not previously observed the ability to control xenografted ALL for a period of as long as 6 months.”

These results led directly to the clinical trial reported last month.

So there you have it, behind the headlines are years of graft by hard-working and innovative scientists, who utilised a wide range of experimental approaches – among which animal studies figure prominently – to develop a novel therapy for CLL. As Professor Bruce Levine points out in the video above, the key to success is often keeping one hand in the basic research lab and the other in the clinic.

Paul Browne

Addendum: Scienceblogger Erv has written an excellent commentary on this study

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PR: Progressive Response

Posted on July 8, 2011 by | Leave a comment

The Metro, a free UK newspaper read by around 3.5 million British commuters each day, today showed why the British public do not find animal research a particularly contentious issue. In less than 200 words,The Metro reported on the use of naked mole rats in the fight against cancer.

The naked mole rat has an inbuilt resistance to tumours and can live for 30 years, compared with the four-year lifespan of similar sized mice. …Early studies suggest the rat’s cells have a tumour resistant capacity absent in other rodents or in humans.

The blunt reporting on this new rodent model for cancer helps to explain why 90% of the British public support animal research. Scientists were also not afraid to put their name to their work. Dr Joao Pedro Magalhaes said:

‘We aim to use the naked mole-rat genome to understand the level of resistance it has to disease, particularly cancer … This might give us more clues as to why some animals and humans are more prone to disease than others… With this work, we want to establish the naked mole-rat as the first model of resistance to chronic diseases of ageing.’

Could molerats hold the key to preventing cancer?

 

The lack of reporting in US media about animal research cannot be blamed solely on the news agencies. Rather that press releases released by universities and research institutions are not taking the time to make the clear link between the medical benefits being developed, and the animal research making it possible.

Cheers

Tom

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