Tag Archives: immunotherapy

Cancer Immunotherapy: A breakthrough made through animal research

The prestigious journal Science has published its top 10 Breakthroughs of the Year 2013, and top of the list is a development that promises to have a huge impact on the lives of millions of people in the coming decades – Cancer Immunotherapy.

The article focuses on three particular therapies that have recently shown great
promise in clinical trials – chimeric antigen receptors, anti-CTLA4 therapy, and anti-PD1 therapy – all of which highlight the fact that his is a field
where animal research is making an absolutely critical contribution.

Regular readers will remember that we discussed how studies in mouse xenograft models of acute lymphoblastic leukaemia (ALL) contributed to the development of chimeric antigen receptor (CAR) therapy that has now shown very promising results in clinical trials against ALL and Chronic Lymphocytic Leukemia, and as Science reports is now being evaluated against many other cancers.

The Science news article on cancer immunotherapy notes that a mouse study published in Science provided key evidence that antibodies that target the protein CTLA-4 – a receptor that acts to suppress the activate the T cells of the immune system – can increase the effectiveness of the immune system in eliminating tumor cells.

Similarly – as discussed in this open access review – the development of anti-PD1 immunotherapy started when was found that PD-1 knockout mice developed autoimmmune disorders, indicating that PD-1 played a role in regulating the immune response. Subsequent preclinical studies in a variety of mouse cancer models demonstrated that administration of antibodies against PD-1 greatly increased the ability of the immune system to attack the tumors, even well established and metastatic tumors.

Laboratory Mice are the most common species used in research

Cancer Immunotherapy – adding even more accomplishments to an already impressive CV!

The examples of CAR, Anti-CTLA4 and anti-PD1 therapies highlight how the field of cancer immunotherapy is maturing, but it is a field which has already delivered some important therapies.  For, example back in 2009 Emma Stokes wrote an article for this blog on the discovery and development of Rituximab, a chimeric antibody therapy that has revolutionized the treatment of B-cell cancers such as Non-Hodgkin’s lymphoma. This work has not stood still either, last week the BBC reported on the successful trial of a new chimeric antibody therapy named GA101 in patients with chronic lymphocytic leukaemia (CLL) and other B-cell conditions. GA101 targets the same protein – CD20 – as Rituximab, but was designed to induce a more powerful anti-cancer activity with fewer adverse effects. The abstract of the 2010 paper reporting on the preclinical research leading to the development of GA101 highlights the role played by studies in mouse models of cancer and in monkeys.

CD20 is an important target for the treatment of B-cell malignancies, including non-Hodgkin lymphoma as well as autoimmune disorders. B-cell depletion therapy using monoclonal antibodies against CD20, such as rituximab, has revolutionized the treatment of these disorders, greatly improving overall survival in patients. Here, we report the development of GA101 as the first Fc-engineered, type II humanized IgG1 antibody against CD20. Relative to rituximab, GA101 has increased direct and immune effector cell-mediated cytotoxicity and exhibits superior activity in cellular assays and whole blood B-cell depletion assays. In human lymphoma xenograft models, GA101 exhibits superior antitumor activity, resulting in the induction of complete tumor remission and increased overall survival. In nonhuman primates, GA101 demonstrates superior B cell–depleting activity in lymphoid tissue, including in lymph nodes and spleen. Taken together, these results provide compelling evidence for the development of GA101 as a promising new therapy for the treatment of B-cell disorders.”

Of course there are another 9 breakthroughs on Science’s list, and it’s notable that several others involve animal research. One of these is CRISPR, a technique that allows scientists to modify the genes of organisms in vivo or cells in vitro with unprecedented precision, and more recently showed potential in mouse studies as a therapy for genetic disorders. Another is CLARITY, a technique that renders brain tissue transparent so that it can be studied in more detail than has previously been possible, and which joins a range of new techniques that are part of a revolution in neuroscience. Of course there was also the news of the first human stem cells created through cloning by Professor Mitalipov at Oregon Health and Science University, a pioneering scientist whose work we have discussed on several occasions.

The choice of cancer immunotherapy, and indeed of this list as a whole, is a reminder at the end of what has been a very difficult year for science in several countries across the world of the extraordinary progress that is being made, and why it is vital to support the scientists who make it happen. As we bid farewell to 2013 and greet 2014 we can only guess at what new discoveries and breakthroughs the year will bring, but we also know that now – perhaps more than any time in recent history – we need to join together across the world to stand up for science!

Paul Browne

The end of cancer? A personal view.

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

A breakthrough against Chronic Lymphocytic Leukemia…thank the mice!

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 lymphoblastic 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