sensitivity to immunotherapy Flashcards
why is determining sensitivity factors important?
Sensitivity to immunotherapies
Benefit of checkpoint varies substantially between and within cancer types
Many patients show no improvement when treated, others show improvement initially then develop resistance, some exhibit durable responses
Important to understand reasons for this allows therapies to be targeted to patients most likely to benefit, prevents unnecessary treatment of patients in which medications are unlikely to be successful
efficacy of CI in different tumour types
• CTLA-4, PD-1 and PD-L1 inhibitors are very effective in melanoma, non-small cell lung cancer and a few other cancer types
• But successes are not universal = efficacy varies depending on tumour of origin
- E.g. PD-1 therapies not effective in prostate cancer = only 5% of cases show substantial tumour shrinkage, compared to 33-45% in melanoma (De Bono et al, 2018)
- Also not effective in hepatocellular carcinoma (Yau et al, 2019) = no statistically significant difference between nivolumab (anti-PD-1) and SMT (sorafenib, tyrosine kinase inhibitor)
TMB
• Thought to be due to differences in TMB
- Melanoma and NSCLC both caused by exogenous/environmental mutagens (UV light, smoking) = cause extensive DNA damage and somatic mutations transformation, invasion, metastasis
- Other cancers, which respond poorly to immunotherapy, have lower mutational burdens (e.g. prostate, breast, thyroid)
• Notable negative correlation between mutational burden and clinical responses to immunotherapy
• More mutations tumours express more neoantigens that T cells can recognise as foreign more potent immune responses when checkpoints are inhibited better outcomes
• Good predictor of immunotherapy sensitivity FDA has now approved pembrolizumab (anti-PD1) for adults and children with TMB-H solid tumours, regardless of histotype = pivotal approval of therapy based on molecular signature alone
• Treatment based on underlying mechanism of malignancy rather than tumour type = arguably a more efficacious way to guide treatment
snyder
2014
• Performed whole genome sequencing on tumour tissue from melanoma patients treated with CTLA-4 antibodies (ipilimumab or tremelimumab)
• High mutational load was associated with significantly increased likelihood of long-term clinical benefit and improved survival in discovery set (25 patients)
• However, validation set (39 patients) showed that high mutational load alone was insufficient to predict long-term benefit = correlation not significant
• Also identified neoepitope signature, consisting of a collection of tetrapeptide neoantigens, only present in patients with long-term clinical benefit = entirely absent from those without clinical benefit strong correlation (P<0.001) between signature and survival in both discovery and validation sets
• Limited sample size (128 exomes sequenced) = correlation might not stay significant in larger patient population
Mismatch repair defects
Le et al (2017) = checkpoint inhibitors are particularly effective against tumours with high mutational loads associated with mismatch repair defects
• evaluated efficacy of pembrolizumab in 86 patients with a range of cancers exhibiting MSH2, MHS6, MLH1 and PMS2 mutations
• impressive results = 53% of patients achieved an objective radiographic response and 77% achieved disease control, with 76% surviving for over a year and 64% for over 2 years
• this trial alone led to PD-1 inhibitors being approved for the treatment of microsatellite-unstable cancers of any origin by the FDA
caution using TMB
Gurajao et al (2020) = note of caution about using TMB as predictor of response
• Analysed whole-exome sequencing data from 501 patients with various cancer types treated with immunotherapy
• TMB only significantly associated with clinical response in melanoma and NSCLC datasets = both potentially confounded by subtypes (stratifying melanoma patients by disease subtype removes association between TMB and clinical benefit)
• Even noted inverse association between TMB and survival in clear renal cell and head and neck cancers, though this was insignificant
• Suggests that FDA approval may deprive patients who would benefit from immunotherapy = other factors also determine sensitivity (e.g. specific mutations, microenvironment etc)
KEYNOTE
Marabelle et al (2020) (KEYNOTE-158 study) = high TBM correlates with immunotherapy response
• Prospective study of 790 patients with advanced treatment-refractory cancers treated with pembrolizumab = stratified into high and low TBM (defined as >10 mutations/Mb)
• Patients with high TBM much more likely to achieve objective responses (29% in high group vs 6% in low group)
• High TMB does not guarantee that patients will respond to immunotherapy = at 24 months, progression-free survival was still only 22% and overall survival only 34% in high TMB group
specific mutations
- Specific mutations
Via genetic profiling of tumours specific mutations have also been correlated with response to checkpoint inhibitors. The personalisation of treatment to specific tumour genotypes has become a foundation of small molecule inhibitor therapy, and ideally could also help improve checkpoint inhibitor therapy efficacy. Blons et al reviewed the relationship between different mutations in NSCLC and found a number of different mutations were indicative of checkpoint inhibitor response13. For example, they found EGFR mutant tumours did not respond to checkpoint inhibition, possibly due to low levels of inflammation in the tumour microenvironment. In contrast BRAF is associated with improved outcomes. This could be due to higher PD-L1 expression found in these tumours. The complex interplay of the genetic changes that take place in tumorigenesis make identifying causality from specific beneficial mutations challenging, and removal of confounding factors such as tumour inflammation, or neoantigen expression almost impossible.
T cell infiltrate
Tumeh et al (2014) = pre-existing CD8+ T cell infiltrate and high expression of PD-1/PD-L1 within a tumour is very important for the efficacy of PD-1
inhibitors
• Immunohistochemistry of pre-treatment samples from 46 metastatic melanoma patients treated with pembrolizumab revealed that responders displayed significantly higher numbers of CD8+, PD-1+ and PD-L1+ cells in the centre and invasive margins of their tumour compared to patients whose disease progressed on the drug
• Despite the small sample size, this study indicates that quantifying CD8, PD-1 and PD-L1 expression may have predictive value in determining the treatment outcome of patients on pembrolizumab
• In contrast, CD4 expression did not correlate with outcomes, suggesting that CD4+ T cells are less important for the success of checkpoint inhibitors.
Topalian et al (2012) = looked at 42 patients treated with anti-PD-1, no response in patients with PD-L1 negative tumours vs 36% response rate in PD-L1 positive tumours
improving T cell infiltrate
The finding that checkpoint inhibitors rely on pre-existing intratumoral CD8+ T cells for efficacy suggests that increasing the recruitment of these lymphocytes to the site of tumours may help overcome drug resistance in some patients.
Tang et al (2016
) = investigated whether targeting tumours with the TNF superfamily member LIGHT would be sufficient to reverse resistance to PD-1 inhibitors
• LIGHT increases the recruitment of naïve T cells from the periphery by activating lymphotoxin β receptor signalling, which in turn increases the expression of attractive chemokines
• treated mice with EGFR-expressing tumours with an anti-EGFR-hmLIGHT fusion protein to specifically target LIGHT and its effects to tumour tissues.
• treatment increased the number of intratumoral CD8+ T cells by as much as 300-500% as measured by flow cytometry and overcame resistance to PD-1 inhibitors in mice with large or non-T cell inflamed tumours, facilitating complete tumour eradication and tumour control respectively
• unclear whether LIGHT therapy would achieve similar efficacy in humans
caution using PD1/PD-L1
BUT predictors do not seem to stand for all cancer types = diversity of these results warrants more investigation into the usefulness of immunohistochemical analysis of PD-1/PD-L1 expression as a clinical indicator
Possible explanation = tumour heterogeneity
Zhang et al (2020)
- reviewed results from 6 RTCs treating NSCLC with PD-1/PD-L1 inhibitors
- found that although PD-L1 expression was indicative of improved response to checkpoint inhibitors, expression did not correlate with overall or progression free survival
Sunshine and Taube (2015). = 15% response rate in PD-L1-ve tumours
