Neoadjuvant atezolizumab conferred increased specific T-cell clone expansion in the tumour compared with pre-treatment among patients with resectable stage IB to stage IIIB non-small cell lung cancer (NSCLC). These data were presented by Dr Feliz Özkan, interventional pulmonologist at the University of Essen, Germany, at the International Association for the Study of Lung Cancer World Conference on Lung Cancer (WCLC 2022) held in Vienna Austria, August 6 – 9, 2022 . In turn, increased T-cell clone expansion which was associated with better pathologic response. Medicom interviewed Dr Özkan about the implications of her results.
Precision medicine has transformed the clinical practice of lung cancer diagnosis and treatment. Increased understanding of driver mutations, coupled with the development of targeted therapies and immunotherapies, have improved outcomes for patients with advanced lung cancer. These therapies have now moved into the earlier stages of lung cancer, including locally advanced disease, and has which in turn is associated with reduced toxicity with steadily better outcomes.
Adjuvant chemotherapy has been approved since the early 2000s but has not been used consistently due to efficacy or toxicity. Increasingly, targeted therapies and immunotherapies, such as atezolizumab (a PD-L1 inhibitor that received FDA approval in 2020 for first-line treatment of adults with metastatic NSCLC) in the phase 3 LCMC3 trial, are being studied in the neoadjuvant and adjuvant settings, with the hope that they may offer a substitute for chemotherapy . For the current analysis, 113 patients with surgically resectable stage Ib to stage IIIb NSCLC received 2 cycles of 1,200 mg atezolizumab prior to surgical exploration for resection, who had pre- vs post-treatment paired samples. The researchers identified individual T-cell clone expansion post-treatment and compared the results with pre-treatment samples from the same individual using T-cell receptor β-chain (TCR) sequencing, and T-Cell Receptor Antigen (MIRA) assays.
The results showed that neoadjuvant atezolizumab in early-stage NSCLC increased specific T-cell clone expansion in the tumour compared with pre-treatment, which was associated with better pathologic response. The number of tumour antigen-specific T-cell clones alone post treatment did not differentiate pathologic responders from non-responders. The authors concluded that understanding T-cell dynamics of atezolizumab response, including tumour subtype-specific differences, may not only predict neoantigen production but also aid in the development of novel therapeutics.
Medicom spoke with Dr Özkan to obtain more information.
What were some of the main findings with regard to T-cell dynamics in response to neoadjuvant atezolizumab in early-stage NSCLC?
“I worked together with Dr David Carbone (Ohio State University, USA) on this and we performed the LCMC3 study (NCT02927301), which is a global phase 2 study with several centres being involved, where we treated patients with neoadjuvant atezolizumab.
There were several biomarker analyses built into the design of LCMC3. For example, we analysed their T-cell receptor sequences before treatment and after 2 cycles of neoadjuvant atezolizumab, both in peripheral blood and in the tumours. We also performed sub-analyses examining non-squamous versus squamous lung cancer subtypes, and whether that was associated with T-cell receptor frequencies, which is the percentage of all T cells compared with all nucleated cells. We also looked at the clonality and at the richness of T cells.
The main findings were that -first of all- we did see differences between non-squamous and squamous cancers regarding their clonality and their T-cell clonality in the tumour and in the blood. Namely, we observed that higher T-cell clonality in the post-treatment tumour tissue was associated with better pathological response in the squamous subtype. We also saw that higher pre-treatment and post-treatment T-cell fractions were associated with better pathological response in the non-squamous subtype.
Another really interesting result was that we performed a neoantigen specific T-cell receptor analysis called the MIRA assay, and we identified more neoantigen specific T-cell receptors in post-treatment than in the pre-treatment peripheral blood samples. Although these data are limited, it was really exciting to see that one of the patients out of the 30 we analysed actually achieved complete pathologic response, and the fact that that single patient also had the highest number of neoantigen positive T-cell receptors, that was very intriguing.
Is the hypothesis that neoantigen T-cell positive receptors are key to achieving response, and does that need to be tested prospectively?
Correct, and this hypothesis needs to be tested in a larger number of patients, for sure. We also applied immune cell signatures derived from the tumour tissue RNA-Seq data, to examine whether there was an association between the tumour tissue T-cell clonality with other immune cells, and whether there was difference by histological subtype. Again, we observed key differences between squamous and non-squamous lung cancers. Furthermore, we saw that there was an association between the enrichment of those immune cells, namely monocytes, macrophages, fibroblasts, neutrophils and natural killer T cells.
What are the next steps and the larger implications?
The next steps still need to be defined, but what we really want to do -and what we have already started doing- is subsequent analyses on the immune cell roles in correlation with the T-cell receptor clonality data and frequency data.
And what does that mean? One of the major takeaways from our data is that is that translational lung cancer research needs to remember that there is much more than just T cells and B cells for robust anti-cancer immune response. We need a lot of immune cells, and they do not all behave the same. We see differences in immune components between non-squamous and squamous tumour subtypes, that may also distinguish their responses to treatment. It would probably make sense to take a deeper dive into subtype-specific research in the future, especially with an eye on potential future treatments.
What do your results say about the mechanisms of disease pathogenesis?
Well, I feel like our numbers here are a little too small, and we also have to account for pre- versus post- treatment heterogeneity. However, what we really see is the effect of atezolizumab treatment on the T-cell receptor clonality and frequency, and there we definitely do see differences. Atezolizumab, just as a reminder, is an anti-PD-L1 drug. We know that adenocarcinomas or the non-squamous subtypes are usually the “hotter” tumours with more tumour-infiltrating lymphocytes than the squamous subtypes, and that information may give us some insight as to why atezolizumab actually does not work as well in the squamous subtypes. Therefore what we possibly lack, is the tumour-infiltrating lymphocytes being effective in the squamous subtypes, they are perhaps less effective than they are in the non-squamous lung cancers. Maybe this will shed further light on that aspect of pathogenesis, and additional studies will help understand this better. Questions that still need to be answered are: How do the T-cell receptor clones that do or do not develop play a role in the local immune response? And are these differences inherent to the cancer cells or the immune environment?
- Özkan F, et al. T-Cell Dynamics in Response to Neoadjuvant Atezolizumab in Early NSCLC by Antigen Response and T-Cell Receptor Sequencing. WCLC2022, abstract OA14.06.
- Provencio M, et al. Treatment Sequencing in Resectable Lung Cancer: The Good and the Bad of Adjuvant Versus Neoadjuvant Therapy. Am Soc Clin Oncol Educ Book. 2022 Apr;42:1-18.
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