Improved Understanding of Biomarkers in Tumor Microenvironment Key for Treatment Decisions in NSCLC

Brian S. Henick, MD

Although PD-L1 has been a key biomarker in determining treatment for patients with non–small cell lung cancer (NSCLC), it is important to address the disparity that exists for patients who do not benefit from immunotherapy. Further research will aim to identify more biomarkers in the tumor microenvironment that could pinpoint patients who would benefit from immunotherapy and prevent unnecessary toxicities in those who would not benefit, according to Brian S. Henick, MD.

“We are probably still just in the infancy of our understanding for how to leverage valuable samples from patients to better understand how to use the tools that we have. Immune checkpoint inhibitors are an incredible tool for a subset of [patients with] lung cancer that have transformed lives. However, the majority of patients who don't have durable benefit are missing out,” Henick said in an interview with OncLive^® following his presentation on immune microenvironment as biomarkers for immunotherapy during the Cellular Therapies and Biomarkers session at the 2023 International Association for the study of Lung Cancer (IASLC) Targeted Therapies of Lung Cancer Meeting.

Henick discussed the importance of expanding on the current knowledge of biomarkers and the tumor microenvironment to enhance treatment approaches for patients with NSCLC and highlighted ongoing research at the Columbia University Herbert Irving Comprehensive Cancer Center aiming to contribute to this growth within this space.

Henick is a medical oncologist, the associate director of Experimental Therapeutics, and the director of Translational Research in Aerodigestive Cancers in Medical Oncology at Herbert Irving.

OncLive: What main message you hoped to convey during your presentation at the 2023 IASLC Targeted Therapies of Lung Cancer Meeting?

Henick: The one thing that I didn't want to get bogged down in too much in this talk was PD-L1. There has been so much on that topic in the field lately, and of course, that is the go-to biomarker that we have. In order for us to get to the next level of understanding, predicting, and improving upon the current treatments that we have, we have to leverage a better understanding of immunology. I tried to survey some of the literature that is not quite there [yet] as far as clinical applicability, but may give us hints on how to better apply what we know.

The main message that I tried to convey is that context matters. When I say context, I mean all of the usual things that one who is developing a biomarker would think about. [The patient] matters. There may be specific factors, such as race/ethnicity, that can impact the immune system’s response to cancer. Context matters in so far as tumor histology and driver mutation status. We see huge differences with respect to immune cell composition with respect to tumor type. Context also matters as far as which immune cells are present within the tumor and what their functional capacity is. There is probably some degree of interplay between…which cells are there, who the [patient] is, what the tumor type is, and the timing and choice of therapy.

[My presentation] was a survey of that complexity and how those factors can impact predictive and prognostic capacity for immune cell subsets.

How could using immune microenvironment as a biomarker for immunotherapy change patient treatment in the future?

Right now, even if we think slightly beyond applications of PD-L1 for lung cancer, we see that localization of PD-L1 with respect to immune cells seems to matter depending on tumor type. In lung cancer, we use the tumor proportion score [TPS], which focuses on the tumor cells that happen to be expressing PD-L1. However, for some of the lung cancer immunotherapy biomarkers, we are using a composite score that incorporates localization of PD-L1 to immune cells. I’m thinking specifically about atezolizumab [Tecentriq] and the tumor cells/immune cells [TCIC] score that they use, and it has been correlated with PD-L1 TPS.

If you think about applications to other tumor types, such as esophageal cancer, head and neck cancer, and others, it is a combined proportion score that is relevant. As we come to better understand the implications of having PD-L1 expressed in different immune cell subsets, it may allow us to refine its use.

For example, there is a study done by the group at Yale [that] observed that the majority of PD-L1 was expressed in tumor associated–macrophages and, in that cohort, the primary driver or predictor of response to immunotherapy may give us a hint as how to better use it.²

On the other hand, novel biomarkers such as the PD-1T TILs subset that has recently been shown to have validated predictive capacity independent of PD-L1, might be a new angle that can be undertaken.³ The hope is that the better we understand these biomarkers, the more we might be able to incorporate them to help an individual patient figure out what treatment to use. We are not quite there yet. We still must validate prospectively for some of these [biomarkers].

Is there any other ongoing biomarker you would like to highlight?

Moving a little bit outside of the immune microenvironment, some of the work that we are doing at the Columbia University Herbert Irving Comprehensive Cancer Center includes looking specifically at T-cell subsets that are marked by TCF1 expression. TCF1 is a marker of T-cell self-renewal. In a small, retrospective study that we conducted, we observed that patients who had T cells—in particular, T-central memory and T-effector memory T cells—who had high levels of TCF1 seem to be more likely to benefit from immunotherapy.

We are currently expanding our retrospective dataset to investigate this further and are planning to look at this prospectively to see if it validates as a predictive biomarker. The hope would be that some of the mouse work that we have done, where we have seen that trying to restore or enhance the population of TCF1-positive T cells seems to associate with increased antitumor immunity, [will lead to prospective studies]. [We plan to look at] different therapeutic strategies to accomplish that in new trials, but we are still a step or two away from that.

Looking to the future, what are some of the main unmet needs that need to be addressed in this space?

At this point, the hope would be to better understand the relationships where there is possibility for confounding of some of these variables. [It will be important] to look at the impact of specific factors, such as race and ethnicity, on the tumor microenvironment. Better understanding the immune system in [different] patients is essential. Similarly, [we need] to further parse out the impact of factors, such as histology and the relative composition of immune cells with respect to markers like PD-L1. Those are the most essential, low-hanging fruit that need to be looked at.

References

1. Henick BS. Immune microenvironment as biomarker for immunotherapy. Presented at: 2023 Targeted Therapies of Lung Cancer Meeting; February 22-25, 2023; Santa Monica, CA.
2. Liu Y, Zugazagoitia J, Ahmed FS, et al. Immune cell PD-L1 colocalizes with macrophages and is associated with outcome in PD-1 pathway blockade therapy. Clin Cancer Res. 2020;26(4):970-977. doi:10.1158/1078-0432.CCR-19-1040
3. Hummelink K, van der Noort V, Muller M, et al. PD-1T TILs as a predictive biomarker for clinical benefit to PD-1 blockade in patients with advanced NSCLC. Clin Cancer Res. 2022;28(22):4893-4906. doi:10.1158/1078-0432.CCR-22-0992