What determines the success of cancer immunotherapy ?

Cancer immunotherapy, a revolutionary treatment that aims to boost the patient’s immune system to enable it to effectively seek and destroy cancer cells, is gaining a lot of interest as an effective treatment that can lead to durable responses in many cancer types.

However, only about 20% of all patients show meaningful benefit, therefore determining factors that impact clinical outcome will undoubtedly extend the benefit of this promising therapy to many more patients. This is particularly important as in many cases patients can experience severe side effects due to the way the treatment works, not to mention the high cost of the drugs themselves.

Cancer immunotherapy works by changing the interaction between the tumor and the immune system in order to tip the balance in favour of the latter. Based on what is known today the following factors are key players in determining how a patent may respond.

1.The features and characteristics of the cancer cells that make up the tumor

These include:

• How visible (or immunogenic) the cancer cells are to the immune system (the more mutations they have, the more foreign (visible) they become and the more likely they are to be attacked).

• Whether the cancer cells are blocking (or suppressing) the attack mounted by the immune cells by increasing the production of molecules that inhibit the activity of the cancer fighting immune cells. For example, increased levels of programmed cell death-1 ligand (PD-L1) on cancer cells which binds to programmed cell death-1 (PD-1) on immune cells and causes their suppression. High levels of molecules such as PD-L1 inhibit anti-cancer immune attack but provide a target for and often predict the success of immunotherapy drugs such as inhibitors of PD-1 and PD-L1.

2. The characteristics of the immune cells in the tumor

Here we need to consider the following:

• The extent to which a tumor is infiltrated by immune cells. “Hot tumors” (those that already have pre-existing immune cell infiltration) are more likely to respond to an immunotherapy treatment than tumors lacking immune cells (also known as “cold tumors” or an “immune desert”).

• The spatial distribution of the immune cells and the need for these to be in close proximity with the target cancer cells for an effective immune attack. Cold tumors as well as “immune excluded” tumors (where immune cells remain at the periphery), respond poorly to immunotherapy.

• The type of the immune cells infltrating the tumors, with the dominance of the cancer-promoting immune cells such as the so-called regulatory T cells and M2 macrophages being an unfavourable situation. On the other hand, prevalence of immune cells bearing cancer-killing capabilities (such as the so-called CD8+ T cells and natural killer cells) and T helper 1-CD4+ T cells is a favorable scenario. In addition, the potential and capacity of the cancer-fighting immune cells to be activated is also key to an effective anti-tumor immune attack.

3. The additional features of the tumor

A key requirement for immune cells to mount an attack on tumors is the ability to reach (infiltrate) the tumour. Tumors with inadequate blood supply (disorganised, inefficient) and those rich in dense collagen fibres (e.g. pancreatic cancers) are often difficult for immune cells to infiltrate. The scarcity of key nutrients that is a feature of many tumors is also a key barrier to effective immune cell activity.

4. The host (the individual patient)

The health of the immune system and the existence of other factors that have a direct impact on it in the patient are also key here. These include:

• The genetic profile of the individual and how this shapes immune cell activity.
• Taking medications that impact immune system fitness (e.g. glucocorticoids, antibiotics)
• Dietary habits which (together with the use of antibiotics) impact the microbes in the gut (these have gained much attention as key regulators of the immune system).

It would seem therefore to be a difficult task to determine with any level of certainty who will definitely respond favorably to immunotherapy, but considering several factor in the above list will be more helpful in predicting likely treatment outcome than looking at a single parameter at any one time.

The features described above also provide opportunities for enhancing the efficacy of immunotherapy by targeting the mechanisms that hinder an effective anti-cancer immune attack. For example administering drugs aimed at tumor blood supply or collagen structure at the same time as immunotherapy has  led to improved responses to immunotherapy.

It is important to bear in mind that tumors evolve over time and so do their interactions with the immune system, so a tumor monitoring approach that incorporates frequent follow-up will undoubtedly help pick up any changes that may necessitate a review of how a patient is managed and the most suitable treatment strategy that will achieve the best results.

References:

McQuade et al, The Lancet Oncology 2019.

Galluzzi et al, Science Translational Medicine 2018.

Mehnert et al, Clinical Cancer Research 2017.