by ecancer reporter Clare Sansom

Not many years ago, cancer immunotherapy would only have been considered of peripheral interest at large clinically-focused cancer meetings such as the NCRI’s main conference.

It is now, however, one of the most important and fast-moving areas in cancer therapy, and it was the common theme of the two final keynote lectures at NCRI 2015.

First to speak was Sergio Quezada from University College London, who chose a deceptively simple title: 'Mobilising Immunity to Fight Cancer'.

After a short introduction in which he described the history of immunotherapy for cancer, he focused on immune checkpoint molecules as cancer targets, taking examples from melanoma and lung cancer.

Immune checkpoints are molecules that modulate the immune system by turning immune signals up or down, and antibodies to these checkpoints can further modulate that response.

The activity of the immune system is controlled by the balance between two types of T cell, regulatory T cells (Treg) that down-regulate the immune response and effector T cells (Teff) that stimulate it.

This balance differs between the tumour micro-environment, lymph nodes and normal tissue; the 'natural' balance in the tumour is in favour of Treg cells

A shift in this balance towards effector T cells correlates with the death (necrosis) of tumour tissue.

Regulatory T cells express high levels of the receptor CTLA-4, and antibodies that inhibit this receptor – such as ipilimumab, which is licensed for the treatment of melanoma – can shift the balance in favour of effector cells to destroy the tumour.

Although this receptor is the best characterised immune checkpoint target, there are many other molecules that contribute to the overall immune response and that can be targeted to 'tweak' the anti-tumour response.

A new antibody therapy, pembrolizumab, which targets the programmed cell death 1 (PD-1) receptor to induce an anti-tumour immune response has been licensed for melanoma and non small cell lung cancer.

An important question to ask, however, is how T cells recognise tumour cells.

All tumours carry a range of tumour-specific antigens (TSAs), and these carry mutations that can differ between the clones in a single tumour.

Anti-TSA antibodies should be good targets for 'cancer vaccines', but they will only be effective if they target antigens that carry mutations that are present in the whole tumour.

The last keynote speaker of the 2015 conference was Carl June from the University of Pennsylvania, USA, who discussed a second important approach to cancer immunotherapy: the therapeutic use of transferred T cells.

T cells or, indeed, any type of cells are very different from other therapeutic agents and so present a different set of challenges to developers and regulators.

Typically, cell therapies are only given once, and effective T cell therapies can persist in the body for many years.

Most T cells kill tumour cells in a 1:1 ratio, so the number of cells available has to be approximately equal to the tumour burden; many early therapies failed because too few cells were used.

Synthetic biology can now been used to engineer therapeutic T cells with specific properties, such as T cells that carry ‘chimaeric antigen receptors' (CARs) with a tumour binding domain and a signalling domain.

The protein CD19, which is found on the surface of and is specific to B cells, is an ideal target for CAR T-cell therapies for both acute and chronic lymphoblastic leukaemia.

After initial trials showed that infusions of CAR-T cells persist and show some activity in leukaemia patients, the therapy was licensed to Novartis for further development.

A significant proportion of adult and child patients treated with this therapy have shown complete and lasting responses, some remaining leukaemia free after over three years.

Side effects include cytokine release syndrome, which causes a high fever, but patients tolerate this as a sign of activity: in fact, there is evidence that patients who do not become feverish do not respond to the therapy.

This therapy has been tested in a small number of patients with multiple myeloma who relapsed after an initial stem cell transplant.

The results for the first two patients were published recently, with one showing a long, stable remission.

This is particularly interesting as multiple myeloma is generally considered to be ‘CD19 negative’: the mechanism of action of the CAR-T cells in this indication is not yet well understood.

June concluded his talk by reporting that 77 clinical trials of CAR-T cells were in progress globally in September 2015, mainly in the US and China.

The NCRI Cancer Conference in 2016 will be held from November 6-9, also at the BT Convention Centre in Liverpool.