Immunomodulatory Effects of Neoadjuvant Nivolumab, Chemotherapy in NSCLC

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The immunomodulatory effects of neoadjuvant immune-based treatments for non–small cell lung cancer (NSCLC) are becoming clearer, in part due to data presented by Schmidt et al at the Society for Immunotherapy of Cancer (SITC) 2021 Annual Meeting (Abstract 962).

The first integrated analysis of tumor immune composition following treatment with neoadjuvant chemotherapy and nivolumab has found that chemotherapy was associated with T-cell immunosuppression and reduced natural killer (NK) cells across all patients, regardless of treatment response. Conversely, the PD-1 inhibitor nivolumab was associated with activation of T-cell populations.

“Regardless of outcome, we observed that chemotherapy is associated with immunosuppression and nivolumab is associated with immune activation,” said lead study author Stephanie T. Schmidt, PhD, Bioinformatics and Genome Engineering, The University of Texas MD Anderson Cancer Center. “When taken together, nivolumab also appears to lessen chemotherapy’s suppressive effects.”

Regardless of outcome, we observed that chemotherapy is associated with immunosuppression and nivolumab is associated with immune activation... When taken together, nivolumab also appears to lessen chemotherapy’s suppressive effects.
— Stephanie T. Schmidt, PhD

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Multiple Cohorts Studied

For this study, Dr. Schmidt and colleagues examined the immunomodulation of neoadjuvant platinum-based chemotherapy, nivolumab, and nivolumab plus chemotherapy—as well as their associations with therapeutic efficacy in resected NSCLC—by integrating immunomic data from the ImmunogenomiC PrOfiling of NSCLC (ICON) study and NEOSTAR trial cohorts.

Three cohorts of patients drawn from ICON and NEOSTAR were considered in this work: patients from ICON who received chemotherapy before surgery, patients from NEOSTAR who received nivolumab, and patients who received nivolumab plus chemotherapy.

For the NEOSTAR cohorts, major pathologic response less than or equal to 10% viable tumor in resected specimens served as the primary endpoint. Across all cohorts, tumors were surgically resected after neoadjuvant treatment. The samples then underwent immune profiling via multiplex immunofluorescence, immunohistochemistry, and flow cytometry. Treatment-associated immunomodulation and associations with therapeutic efficacy were analyzed using modality specific approaches and statistical testing.

Using MetaCyto to examine the effect of chemotherapy across all cohorts controlling for nivolumab, Dr. Schmidt and colleagues found that chemotherapy was associated with immunosuppression, increasing PD-1­–positive T-cell populations.

“After controlling for nivolumab, we saw increased PD-1–positive populations for regulatory, helper, and effector T cells, in addition to PD-1–positive non–tissue resident populations of effector and helper T cells,” said Dr. Schmidt. “We also observed that chemotherapy decreases NK-cell populations.”

According to Dr. Schmidt, these trends were shared across all patients, including nonresponding patients. However, the effect sizes of PD-1–positive populations were modestly increased in nonresponders compared to the overall population, suggesting a potentially even more immunosuppressive environment in these patients, said Dr. Schmidt.

Conversely, after controlling for chemotherapy across all cohorts, data showed that nivolumab was associated with immune activation for all patients, increasing inducible costimulatory (ICOS)-positive regulatory, helper, and effector T cells in addition to tissue-resident and non–tissue resident ICOS-positive effector T cells and non–tissue resident ICOS-positive helper T cells.

“Comparing nivolumab and nivolumab plus chemotherapy directly revealed that, across all patients, regardless of outcome, adding chemotherapy may drive exhaustion by increasing temporary positive regulatory, helper, and effector T cells,” said Dr. Schmidt.

Considering the additional modalities of immunohistochemistry and multiplex immunofluorescence, the researchers also saw marked decreases in the percentage of cells expressing PD-L1 when nivolumab and chemotherapy were combined, in contrast to the range of values observed when each is administered independently.

“In conjunction with the immunosuppressive effects of chemotherapy noted earlier, this could be seen as nivolumab providing a moderating effect,” said Dr. Schmidt.

Dr. Schmidt and colleagues are currently developing an integrated network of flow cytometry, multiplex immunofluorescence, and immunohistochemistry data which promises to further augment translational insights for neoadjuvant chemoimmunotherapies.

Disclosure: Dr. Schmidt reported no conflicts of interest.


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