Effectiveness of Immunotherapy Cancer Treatment May Vary With Genetics

A new study has shown that a person’s genes may affect their likelihood of immunotherapy cancer treatment being successful[i] [ii].

Immunotherapy is a term that refers to treatments in which the body’s immune system is activated in order to fight disease.  In previous issues of BCDN, we have discussed in detail the use of a particular type of immunotherapy, known as PD-L1 checkpoint inhibition, in the treatment of mesothelioma.  This was discussed in issues 167 and 176 and reviewed most recently in issue 208.  Though it has received some approvals for treatment of certain lung cancers, treatment of mesothelioma is generally experimental.  Some clinical trials of checkpoint inhibition as treatment for mesothelioma have produced optimistic results.  It should be noted that this treatment is intended to extend life and improve quality of life, rather than to provide a cure.  The treatment is expensive, and there is the potential for it to appear in living mesothelioma claims in the near future.

The potential use of checkpoint inhibitors in the treatment of mesothelioma is promising because one trial showed disease control (disease either improves or remains stable) in 76 % of patients.  However, there is large variation in the effectiveness of the treatment between patients.  Given that the treatment currently costs around £70,000, it is important to try to determine which patients are likely to benefit, and which are not.

PD-L1 checkpoint inhibition works by blocking an interaction between a protein on cancer cells known as PD-L1 and immune cells, in which the immune cells are instructed not to attack the cancer cell.  This means that the immune cells can then attack the cancer cells.  Thus, it follows that the treatment would be expected to be effective in those patients whose cancer cells have the PD-L1 protein.  Indeed, this is part of the selection criteria when lung cancer patients are selected for PD-L1 checkpoint inhibition treatment; only those whose tumours have PD-L1 expression in 50 % or more of the cells are eligible for first-line treatment on the NHS[iii].  A small study of 36 mesothelioma patients found a clear correlation between PD-L1 expression and response to a PD-L1 inhibitor drug, whereby patients with greater PD-L1 expression were more likely to respond[iv].  The amount of PD-L1 on cancer cells is usually determined by biopsy, but it may also be possible to identify suitable patients using cheap and noninvasive computer-based imaging techniques (BCDN issue 206)[v].  However, it appears that patient selection may not be this simple: for example, a recent study demonstrated that the amount of PD-L1 on mesothelioma tumour cells may change over time in about 20 % of patients[vi] [vii]. It has also been shown (by some of the authors from the new study) that the magnitude and type of damage to cells are associated with response to checkpoint inhibitor treatment[viii].  Now, a study published in December 2017 has reported that an individual’s own genes can play a role in the response to immunotherapy drugs.

The genes of interest are part of a gene system known as the human leukocyte antigen (HLA) system, which produces proteins that the immune system uses to distinguish between body cells and foreign cells.  HLA genes have many possible variations, and there are hundreds of different versions that someone may have.  The study looked at 1,535 cancer patients (various types of cancer) treated with checkpoint inhibitors and found that patients who had more varied versions of the HLA genes responded better to the treatment.  There were also effects due to the patient’s genes and the mutations in the tumour itself: patients with fewer different HLA genes and fewer tumour mutations did not respond as much to checkpoint inhibitor treatment.  In addition, among melanoma patients, HLA genes also affected survival.

This study adds more information to the growing body of literature regarding which cancer patients would be likely to benefit from checkpoint inhibition immunotherapy.  This may be of significance for living mesothelioma claimants.

  1. In the absence of toxicological information, implement the highest level of control to prevent workers from any exposure.  Where more information is available, take a tailored approach.
  2. Take control measures based on the principle of hierarchy of controls, meaning that the first control measure should be to eliminate the source of exposure before implementing control measures that are more dependent on worker involvement, with PPE being used only as a last resort.
  3. Prevent dermal exposure by measures such as surface cleaning and use of appropriate gloves.
  4. When assessment by a workplace safety expert is not available, use control banding for nanomaterials to select exposure control measures in the workplace. [Control banding is a risk management approach to identify and recommend exposure control measures for potentially hazardous substances for which toxicological information is limited].

Regarding health surveillance, the Guideline Development Group (GDG) could not make a recommendation for targeted MNM-specific health surveillance programs over existing health surveillance programmes that are already in use, due to the lack of evidence.

Regarding training and involvement of workers, the GDG considers training of workers and worker involvement to be best practice, but cannot recommend one form of training over another, due to the lack of studies available.

It is expected that there will be considerable progress in validated measurement methods and risk assessment.  Therefore, the GDG proposes to update these guidelines in five years’ time.

 

[i] Chowell, D. et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science eaao4572 (2017). doi:10.1126/science.aao4572  http://science.sciencemag.org/content/early/2017/12/06/science.aao4572 (Accessed 23 December 2017)

[ii] Cancer Immunnotherapy may work better in patients with specific genes. ScienceDaily 15 December 2017 https://www.sciencedaily.com/releases/2017/12/171215094518.htm (Accessed 16 December 2017)

[iii] National Institute for Health and Care Excellence, Final appraisal determination,

Pembrolizumab for untreated PD-L1- positive metastatic non-small- cell lung cancer. May

  1. https://www.nice.org.uk/guidance/ta447/documents/final-appraisal-determination-document (Accessed 16th November 2017)

[iv] Quispel-Janssen, J. et al. OA13.01 A Phase II Study of Nivolumab in Malignant Pleural Mesothelioma (NivoMes): with Translational Research (TR) Biopies. Journal of Thoracic Oncology 12, S292–S293 (2017). http://www.jto.org/article/S1556-0864(16)31541-6/fulltext (Accessed 21 November 2017)

[v] Computer programme could predict if immunotherapy will work. Cancer Research UK. 27 October 2017. http://www.cancerresearchuk.org/about-us/cancer-news/news-report/2017-10-27-computer-programme-could-predict-if-immunotherapy-will-work   (Accessed 30th October 2017).

[vi] Terra, S. B. S. P., Mansfield, A. S., Dong, H., Peikert, T. & Roden, A. C. Temporal and spatial heterogeneity of programmed cell death 1-Ligand 1 expression in malignant mesothelioma. OncoImmunology 6, e1356146 (2017). http://www.tandfonline.com/doi/abs/10.1080/2162402X.2017.1356146 (Accessed 23 December 2017)

[vii] Study Highlights Challenge of Selecting Patients for Mesothelioma Immunotherapy.  Surviving Mesothelioma.com, 20 November 2017. https://survivingmesothelioma.com/study-highlights-challenge-selecting-patients-mesothelioma-immunotherapy/ (Accessed 21 November 2017)

[viii] Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science 348, 124–128 (2015). http://science.sciencemag.org/content/348/6230/124 (Accessed 23 December 2017)