Improving outcome of cancer immunotherapy through drug combinations

Cancer immunotherapy is a new type of treatment aimed at bolstering the immune system to enable it to more effectively detect and destroy tumours. This type of therapy has shown unprecedented activity in many cancer types in a fashion that was never seen before.

Unfortunately, only about 20% of all patients benefit from immunotherapy and much more needs to be done to increase tumour susceptibility to this revolutionary anti-cancer treatment.

Under normal circumstances or when treated with immunotherapeutic drugs, tumours develop an ability to evade immune control and this occurs via broadly two main mechanisms:

Mechanism 1: Changes within the cancer cells themselves

These are changes in the cancer cells that can dampen down the activity of immune cells that would otherwise kill tumours, or decrease their visibility to immune cells in the first place.

An example of this is the increased expression of the protein called PD-L1 on cancer cells which interacts with the PD-1 molecule on the so-called CD8 T cells (the main driver of cancer immunity) suppressing their ability to attack and destroy the tumour.

Mechanism 2: Changes in the tumour growth environment

These are triggered by the action of cancer cells on their surrounding neighborhood (also known as the tumour microenvironment), making it detrimental to incoming immune cells, which become unable to reach or mount an effective attack against cancer cells.

An example of this is the increased consumption by tumour cells of the amino acid tryptophan via increased levels of the enzyme indoleamine 2,3-dioxygenase (IDO). Tryptophan is a fuel for immune cells and its scarcity decreases the ability of the cancer-fighting CD8 T cells to work effectively whilst enabling the expansion of the cancer-promoting regulatory T cells.

Another example is the increased production by cancer cells (and other tumour-coerced cell types) of the cell-to-cell communication protein TGF-beta (TGF-β), which can cripple the activity and killing capacity of CD8 T cells.  TGF-β can also stimulate the laying down of a “barrier-like” collagen around the tumour in the extracellular space which prevents immune cell penetration and insulates cancer cells from immune attack.

There are many types of cancer immunotherapy strategies which are broadly aimed at either mechanism (i), e.g. PD-L1 and PD-1 checkpoint inhibitors, or mechanism (ii), e.g. TGF-β or IDO inhibitors.

To curb the ability of cancer cells to evade immune attack and increase the effectiveness of cancer immunotherapy, it would therefore seem beneficial to attack both of these mechanisms at the same time, so the cancer has little chance of escape.

Indeed, many clinical trials are now testing cancer immunotherapy strategies that are aimed at more than one target or mechanism, with the hope that these will produce better responses in patients.

One trial that looks particularly promising is evaluating a drug called M7824 (GlaxoSmithKline), which is aimed at blocking both PD-L1 and TGF-β simultaneously.

The drug acts as a “trap” in the tumour microenvironment reducing the availability and action of TGF-β and, at the same time, blocking PD-L1. Data obtained in mice [1] suggest that M7824 may be more effective at halting tumour growth than drugs aimed at either TGF-β or PD-L1 alone particularly when used as a cocktail with anti-cancer vaccines.

In phase I patient trials, M7824 showed a similar safety profile to other immunotherapy drugs and that it can be effective in different cancer types [1].

Phase II trials which will a include more patients will examine the efficacy of M7824 in combination with anti-cancer vaccines [1]. The results of these studies will be crucial in determining the value and effectiveness of this promising immunotherapy drug.

Combination treatment using other mechanisms

Another strategy in combination therapy is to combine immunotherapy with the more traditional ways of cancer treatment, such as radiotherapy, chemotherapy and molecular-targeted drugs. The latter are aimed at the unique molecular abnormalities required to drive and sustain the development of each patient’s tumour as opposed to treatment that aim to kill cells in a blunt manner (hence the “targeted” notion).

For example, in advanced stage breast cancer with high levels of the cellular protein HER2, also know as HER2 positive breast cancer, combination of trastuzumab, an antibody aimed at HER2, with the PD-1 checkpoint inhibitor pembrolizumab in early stage clinical testing (phase Ib-II) was effective in some patients who had previously stopped responding to trastuzumab-based treatment [2].

The benefit in this case was mostly confined to patients with tumours that were also positive for PD-L1 with no responses seen in another group of HER2 positive breast cancer patients where the tumours tested negative for PD-L1 [2].

The results are clearly encouraging but need to be confirmed in subsequent larger studies with improved design, selection of patient and PD-L1 testing strategies [2].

When it comes to cancer treatment, a combinatorial approach with drugs aimed at several targets is always more effective than a single agent. Immunotherapy would seem to be no exception.

References:

[1] Karin M. Knudson, Kristin C. Hicks, Xiaoling Luo, Jin-Qiu Chen, Jeffrey Schlom, Sofia R. Gameiro. M7824, a novel bifunctional anti-PD-L1/TGFβ Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine. OncoImmunology. 2018; 7(5): e1426519. doi: 10.1080/2162402X.2018.1426519

[2] Sherene Loi, Anita Giobbie-Hurder, Andrea Gombos, Thomas Bachelot, Rina Hui, Giuseppe Curigliano, Mario Campone, Laura Biganzoli, Hervé Bonnefoi, Guy Jerusalem, Rupert Bartsch, Manuela Rabaglio-Poretti, Roswitha Kammler, Rudolf Maibach, Mark J Smyth, Angelo Di Leo, Marco Colleoni, Giuseppe Viale, Meredith M Regan, Fabrice André. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b–2 trial. The Lancet Oncology. 2019; 20(3): 371-382. doi: 10.1016/S1470-2045(18)30812-X