The Shocking Effect of Boiled Bugs

There’s never a dull moment in science – well, not many – and at the moment no field is fizzing more than immunotherapy. Just the other day in Outsourcing the Immune Response we talked about the astonishing finding that cells from healthy people could be used to boost the immune response – a variant on the idea of taking from patients cells that attack cancers, growing them in the lab and using genetic engineering to increase potency (generally called adoptive cell therapy).

A general prod

Just when you thought that was as smart as it could get, along comes Angus Dalgleish and chums from various centres in the UK and Spain with yet another way to give the immune system a shock. They used microorganisms (i.e. bugs) as a tweaker. The idea is that bacteria (that have been heat-killed) are injected, they interact with the host’s immune system and, by altering the proteins expressed on immune cells (macrophages, natural killer cells and T cells) can boost the immune response. That in turn can act to kill tumour cells. It’s a general ‘immunomodulatory’ effect. Dalgleish describes it as “rather like depth-charging the immune system which has been sent to sleep”. Well, giving it a prod at least.

bugs-pic

Inactivating bugs (bacteria) and waking up the immune system.

And a promising effect

The Anglo-Spanish effort used IMM-101 (a heat-killed suspension of a bacterium called Mycobacterium obuense) injected under the skin, which has no significant side-effects. The trial was carried out in patients with advanced pancreatic cancer, a disease with dismal prognosis, and IMM-101 immunotherapy was combined with the standard chemotherapy drug (gemcitabine). IMM-101increased survival from a median of 4.4 months to 7 months with some patients living for more than a year and one for nearly three years.

Although the trial numbers are small as yet, this is a very exciting advance because it looks as though immunotherapy may be able to control one of the most serious of cancers in which its incidence nearly matches its mortality.

References

Dalgleish, A. et al. (2016). Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer. British Journal of Cancer doi: 10.1038/bjc.2016.271.

 

Advertisements

Outsourcing the Immune Response

We’re very trendy in these pages, for no other reason than that the idea is to keep up to date with exciting events in cancer biology. Accordingly, we have recently talked quite a lot about the emerging field of cancer immunotherapy – the notion that our in-built immune system will try to kill cancer cells as they emerge, because it ‘sees’ them as being to some extent ‘foreign’, but that when tumours make their presence known it has not been able to do the job completely. The idea of immunotherapy is to give our in-house system a helping hand and we’ve seen some of the approaches in Self Help – Part 2 and Gosh! Wonderful GOSH.

The immune see-saw

Our immune system walks a tight-rope: on the one hand it should attack and eliminate any ‘foreign’ cells it sees (so that we aren’t killed by infections) but, on the other, if it’s too efficient it will start destroying out own cells (which is what happens in auto-immune diseases such as Graves disease (overactive thyroid gland) and rheumatoid arthritis.

Like much of our biology, then, it’s a tug-of-war: to kill or to ignore? And, like the cell cycle that determines whether a cell should grow and divide to make two cells, it’s controlled by the balance between ‘accelerators’ and ‘brakes’. The main targets for anti-tumour immune activity are mutated proteins that appear on the surface of cancer cells – called neo-antigens (see The Shape of Things to Come?)

The aim of immunotherapy then is to boost tumour responses by disabling the ‘brakes’. And it’s had some startling successes with patients going into long-term remission. So the basic idea works but there’s a problem: generally immunotherapy doesn’t work and, so far, in only about one in ten of patients have there been significant effects.

Sub-contracting to soup-up detection

Until now it’s seemed that only a very small fraction of expressed neo-antigens (less than 1%) can turn on an immune response in cancer patients. In an exciting new take on this problem, a team of researchers from the universities of Oslo and Copenhagen have asked: “if someone’s immune cells aren’t up to recognizing and fighting their tumours (i.e. ‘seeing’ neo-antigens), could someone else’s help?” It turns out that many more than 1 in 100 neo-antigens are able to cause an immune response. Even more exciting (and surprising), immune cells (T cells) from healthy donors can react to these neo-antigens and, in vitro at least (i.e. in cells grown in the laboratory), can kill tumour cells.

118. pic

Genetic modification of blood lymphocytes

T cells are isolated from a blood sample and novel genes inserted into their DNA. The engineered T cells are expanded and then infused into the patient. In the latest development T cells from healthy donors are screened for reactivity against neo-antigens expressed in a patient’s melanoma. T cell receptors that  recognise neo-antigens are sequenced and then transferred to the patient’s T cells.

How does that work?

T cells (lymphocytes) circulating in the blood act, in effect, as scouts, scanning the surface of all cells, including cancer cells, for the presence of any protein fragments on their surface that should not be there. The first contact with such foreign protein fragments switches on a process called priming that ultimately enables T cells to kill the aberrant cells (see Invisible Army Rouses Home Guard).

What the Scandinavian group did was to screen healthy individuals for tissue compatibility with a group of cancer patients. They then identified a set of 57 neo-antigens from three melanoma patients and showed that 11 of the 57 could stimulate responses in T cells from the healthy donors (T cells from the patients only reacted to two neo-antigens). Indeed the neo-antigen-specific T cells from healthy donors could kill melanoma cells carrying the corresponding mutated protein.

What can possibly go wrong?

The obvious question is, of course, how come cells from healthy folk have a broader reactivity to neo-antigens than do the cells of melanoma patients? The answer isn’t clear but presumably either cancers can make T cell priming inefficient or T cells become tolerant to tumours (i.e. they see them as ‘self’ rather than ‘non-self’).

And the future?

The more critical question is whether the problem can be short-circuited and Erlend Strønen and friends set about this by showing that T cell receptors in donor cells that recognize neo-antigens can be sequenced and expressed in the T cells of patients. This offers the possibility of a further type of adoptive cell transfer immunotherapy to the one we described in Gosh! Wonderful GOSH.

https://cancerforall.wordpress.com/2015/11/19/gosh-wonderful-gosh/

As one of the authors, Ton Schumacher, put it “Our findings show that the immune response in cancer patients can be strengthened; there is more on the cancer cells that makes them foreign that we can exploit. One way we consider doing this is finding the right donor T cells to match these neo-antigens. The receptor that is used by these donor T-cells can then be used to genetically modify the patient’s own T cells so these will be able to detect the cancer cells.”

And Johanna Olweus commented that “Our study shows that the principle of outsourcing cancer immunity to a donor is sound. However, more work needs to be done before patients can benefit from this discovery. Thus, we need to find ways to enhance the throughput. We are currently exploring high-throughput methods to identify the neo-antigens that the T cells can “see” on the cancer and isolate the responding cells. But the results showing that we can obtain cancer-specific immunity from the blood of healthy individuals are already very promising.”

References

Strønen, M. Toebes, S. Kelderman, M. M. van Buuren, W. Yang, N. van Rooij, M. Donia, M.-L. Boschen, F. Lund-Johansen, J. Olweus, T. N. Schumacher. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science, 2016.

“Fighting cancer with the help of someone else’s immune cells.” ScienceDaily. ScienceDaily, 19 May 2016.