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Fighting cancer like an infection

Professors Irv Weissman and Ravi Majeti at Stanford University and Professor Paresh Vyas at the MRC Molecular Haematology Unit in Oxford, are working on an antibody from the Stanford investigators that enables the immune system to detect and kill cancer cells. They are now testing whether it’s safe and effective for use in people with blood cancer. In this week’s blog they tell us how they collaborated across the Atlantic to get public funding for a project that has led to a spin out with multiple backers and a promising clinical trial.

Immune cells start to recognise and destroy a tumour

What if we could make our immune system fight cancer like it fights infection?

These aren’t the only teams in the world grappling with that question but for Professor Irv Weissman and Professor Paresh Vyas, the solution feels tantalisingly close for patients with blood cancer.

Irv’s team in Stanford has developed an antibody that enables our immune systems to detect and kill cancer cells. It worked in the dish, Paresh’s team found it worked in mice bearing human leukaemia cells, and now they’re conducting a clinical trial in the UK in patients with acute myeloid leukaemia (AML) – the most aggressive form of blood cancer.

Blood cancer’s beginnings

Professor Paresh Vyas

Professor Paresh Vyas

“In a healthy person, mature blood cells are constantly being created and replaced in a process called haematopoiesis,” Paresh explains. “Irv’s lab in Stanford was the first in the world to identify and isolate blood-forming stem cells in mice, and to map how blood develops. They mapped out that stem cells make progenitor cells, a more specialised type of stem cell, which make our mature blood cells.

“In a person with AML, something goes wrong early on in this process – the stem cells mutate and create bad versions of the progenitor cells. The mutated progenitor cells produce many many copies of themselves, eventually making cancer stem cells.”

How cancer cells stay under the radar

In most cases, our immune systems are pretty good at spotting cells that are damaged, inflamed, or malignant. Our immune response sends immune cells called macrophages to engulf and destroy the damaged cells, keeping us healthy. However, cancer stem cells, and the cells and tumours they produce, manage to escape this clean-up process by emitting a signal that tells our immune system ‘don’t eat me’, overriding the less powerful ‘eat me’ signal that the macrophages normally respond to. And it works – our immune systems leave the cancers alone and they move on to find another target.

Professor Irving Weissman

Professor Irving Weissman. Credit: Steve Fisch

“We found that this signal was caused by a protein called CD47,” Irv tells us, “which covers the surface of the cancer stem cells and the mature stem cells. Chemotherapy usually kills off most of the cancer cells, but the cancer stem cells often survive – allowing the cancer to return. We reasoned that if we could block the CD47 signal, the immune system would be able to fight the cancer stem cells and the tumours they cause.”

A common target is a promising target

“This was an exciting prospect,” Paresh says, “but we needed to know how frequently CD47 occurred on cancer cells in people with AML. If it was only a very small proportion then it wouldn’t be a useful target. So my team in Oxford tested 500 blood samples from patients with AML. We found that CD47 was the only protein on the cell surface that every single sample had in common.”

Irv explains: “In something like cancer, which changes constantly, to find that all the samples had a target in common was almost too good to be true. Even better, where cancers can become resistant to drugs because cancer cells stop making the protein that the drug targets – if cells stopped making CD47, the ‘don’t eat me signal’ would disappear. That would allow the immune system to move in and attack without any need for the drug.

“We made the antibody we’re using in the clinical trial, Hu5F9-G4, in Stanford. It works by blocking CD47’s ‘don’t eat me’ signal, alerting the macrophages to target the cancer cells. Paresh’s team worked on finding which patients could benefit from the antibody and designed the clinical trial. To help the body fight the cancer, my team has also developed a number of other antibodies to attack different targets on the cancer cells. These antibodies could be used in future trials to work alongside anti-CD47 antibodies.”

From dish to mouse to human

Paresh’s team collaborated with the Stanford team in conducting the pre-clinical tests needed before the drug went to trial in patients. “Our tests found that the antibody was very safe in mice and that it eliminated the human AML cells when they were transplanted into mice. This was very encouraging and supported the case for a trial in patients. Of course we will only know about safety and efficacy in humans after the trials in patients are completed.

“Though there is no perfect way of testing new drugs, special care has to be taken when testing a brand new type of drug (so-called first-in-class) to make sure they are safe, before being given to a patient. Testing human cells ‘in a dish’ is a useful part of this process, but it can’t tell us how a living organism will handle the drug. That’s why all health regulatory authorities want to see information on how drugs are handled in living organisms.”

Finding the funds

Although things are looking promising now, Irv tells us that it wasn’t easy to get their project started: “We really struggled to get this project funded at first. Without public funding from the California Institute of Regenerative Medicine and the MRC, this project would have been dead from the beginning. We couldn’t even get sustained research funding from the usual US government sources, much less the levels needed for two academic groups to take the work through preclinical proof-of-principle testing, preclinical toxicity testing and to applying for approval to begin trials.”

But now fortunes have turned and Irv has founded Forty Seven Inc., an immuno-oncology company: “We’ve secured $75 million in external investment, including from Google’s independent venture arm ‘GV’, to license rights from Stanford University for the anti-CD47 drug, and several other antibodies we have developed in Stanford to attack cancer in different ways, helping the immune system to wipe out cancer cells.

 “This has not only been an experiment in research and therapy development, but a test of how academic groups can fund research to, and through, early phase clinical trials enabling other sources to enter at a point when we have minimized any financial risk and shown how effective the intervention could be.”

High hopes

The two are hopeful that the antibody might work in all cancers. “But there is, of course,” explains Paresh, “lots of work to do to understand and realise this potential. At the moment, we hope that this antibody becomes therapeutic for AML, changing the grim outcome for patients into the prospect of a prolonged remission with a potential cure. We also hope that this work leads our collaborations to develop new cancer and leukaemia therapies through further joint clinical trials.”

This study received MRC funding as part of the Biomedical Catalyst scheme.
The clinical trial in patients with AML has also been part funded by the charity Bloodwise.

Sylvie Kruiniger

2 Comments Post a comment
  1. Chandravinod Pathak, Architect #

    Congratulations to team of Prof. Paresh Vyas,Prof.Irving Weissman for developing antibodies that enables the immune sytem to detect and kill blood cancer cells.

    The article was forwarded to me by Prof. Paesh Vyas’s father. It is a great achievement by the team.

    From:
    cvpathak@gmail.com
    (Vadodara, India)

    June 11, 2016

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