AACR Posters Demonstrate CGP for Biomarker Detection and Multiomics Profiling

Posters from the American Association of Cancer Research (AACR) Annual Meeting demonstrated that the use of genomic profiling and sequencing can detect immunotherapy biomarkers and predict clinical outcomes in patients with cancer.

CGP for NSCLC Immunotherapy Biomarkers

Comprehensive genomic profiling (CGP) was performed for 64,062 patients with non-small cell lung cancer (NSCLC), 59% of whom had lung biopsies (LB), 25% had metastatic site biopsies, and 17% had regional or distant lymph node biopsies. Researchers assessed the samples of 386 patients with lung or metastatic biopsies and determined tumor mutational burden (TMB).

Of the metastatic biopsy (MB) samples examined, 23% were from the liver, 23% were from the brain, 15% came from bones, 14% were soft tissue samples, 8% were from glands and other rare sites.

Patients with MBs were observed to have elevated TMB compared to patients with LBs, most notably in the brain, adrenal gland, and kidney. However, TMB in the liver MBs was similar to LBs. Heterogeneity in programming death 1 expression was observed higher in the head and neck, adrenal gland, lymph nodes, and soft tissue compared to LBs.

Liver MB had fewer KRAS alterations compared with LBs (21% vs 31%; P < .0001). Also, brain MBs had higher rates of KRAS (37% vs 31%; P < .0001), KEAP (16% vs 9%; P < .0001), and STK11 alterations (23% vs 15%; P < .0001). Genes that are known to have a possible role in metastatic spread, including SMARCA4, RICTOR, and PIK3CG, were identified to be higher in specific MBs than LBs.

Multiomics Profiling for Mantle Cell Lymphoma

Researchers performed single cell transcriptomic profiling for longitudinally collected primary samples (n = 39) from 15 patients with mantle cell lymphoma to see whether they would have a response or relapse to brexucabtagene autoleucel (BA) chimeric antigen receptor T-cell (CAR T) therapy.

The results showed that the CD4/CD8 cytotoxic T cells in total immune cells were significantly reduced at relapse compared to those at pretreatment or at BA remission. Data from upregulated immune checkpoint TIGIT, CD96, and LAG3 in CD4/CD8 cytotoxic T cells and ex vivo stimulation showed acquisition of exhausted T cell state at relapse.

However, a significantly higher myeloid cells were observed in relapse samples compared to samples from pretreatment or at BA remission. Also, myeloid-derived suppressive cells (MDSCs) were higher at relapse.

The researchers said that the data may suggest that tumor immune may initiate at relapse by inducing a state of T cell exhaustion and expanded MDSCs. Additionally, a longitudinal profiling panel of soluble checkpoint cytokines from plasma samples found that PD-L1, PD-L2, TIM3, and LAG3 were significantly decreased at remission compared to baseline and resurrected back to baseline at relapse.

Moreover, soluble IL2 receptor (sIL2R) was significantly reduced at remission but was elevated at relapse at levels that were higher than at baseline. Ex vivo stimulation demonstrated that IL-2 plus sIL2R enhanced cell growth compared to IL-2 or sIL2R alone in the sample collected at pretreatment, suggesting that sIL2R may play a suppressive function for T cell expansion and activation.

The study was the first to report on exploring potential mechanisms of resistance to therapy with BA in patients with mantle cell lymphoma.

Reference

Kaplan BG, Huang RSP, Dennis L, et al. Comprehensive genomic profiling (CGP) reveals site-specific enrichment of immunotherapy biomarkers and targetable alterations in non-small cell lung cancer (NSCLC) metastasis. Presented at AACR 2022 Annual Meeting. April 8-12, 2022; New Orleans, Louisiana. Abstract: 753/9.

Jiang VC, Hao D, Jain P, et al. Multi-omics profiling can predict for relapse and response to brexucabtagene autoleucel CAR T-cell therapy in patients with mantle cell lymphoma. Presented at AACR 2022 Annual Meeting. April 8-12, 2022; New Orleans, Louisiana. Abstract: 771/27.