Prospects for personalized combination immunotherapy for solid tumors based on adoptive cell therapies and immune checkpoint blockade therapies

26 Background: Immune checkpoint blockade (ICB) therapy has been effective patients with solid tumors. Currently, tumor expression of programmed death-ligand 1 (PD-L1) is clinically used as a biomarker of predicted response to ICBs in non-small cell lung cancer (NSCLC). However, across solid tumors, only a subset of patients benefit from ICBs, so there is need to identify other biomarkers to predict response to ICB. We investigated the use of large panel next generation sequencing (NGS) to characterize biomarkers to ICBs across solid tumors. Methods: NGS and PD-L1 immunohistochemistry (IHC) was performed on a series of solid tumors. NGS analysis included detection of single nucleotide polymorphisms (SNPs), insertions and deletions (indels), copy number variation (CNV), and gene-fusions in 435 cancer-related genes, microsatellite instability (MSI), tumor mutational burden (TMB) based on non-synonymous SNPs, and HPV16/18 and EBV viral status. Genomic alterations in previously reported biomarkers of response to ICBs were assessed. Results: 143 solid tumors were analyzed with NGS and PD-L1 IHC. The samples included 80 NSCLC, 15 colorectal carcinoma, 8 cutaneous melanoma, 6 breast carcinoma, and 34 other solid tumors. The mean TMB varied by tumor type, with the highest in melanoma. The frequency of PD-L1 expression was higher in NSCLC and melanoma compared to colorectal carcinoma. The relationship between PD-L1 expression and the other biomarkers varied by tumor type (Table 1). Positive association (+); Negative association (-): No association (None). Conclusions: We characterized biomarkers to ICBs across a range of solid tumors. We found tumor-specific differences in the mean TMB and frequency of PD-L1 expression. We also found tumor-specific differences in the associations between PD-L1 and other potential biomarkers, including KRAS, NRAs, HRAs, BRAF, and EGFR mutation status. We found no correlation between PD-L1 expression and MSI and viral status. NGS is an efficient platform for analysis of biomarkers in solid tumors.[Table: see text]

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Intratumoral expression of IL-7 and IL-12 using an oncolytic virus increases systemic sensitivity to immune checkpoint blockade

Science Translational Medicine ◽

10.1126/scitranslmed.aax7992 ◽

2020 ◽

Vol 12 (526) ◽

pp. eaax7992 ◽

Cited By ~ 12

Author(s):

Shinsuke Nakao ◽

Yukinori Arai ◽

Mamoru Tasaki ◽

Midori Yamashita ◽

Ryuji Murakami ◽

...

Keyword(s):

Antitumor Activity ◽

Vaccinia Virus ◽

Solid Tumors ◽

Immune Checkpoint ◽

Immune Status ◽

Tumor Regression ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Complete Tumor Regression ◽

Complete Tumor

The immune status of the tumor microenvironment is a key indicator in determining the antitumor effectiveness of immunotherapies. Data support the role of activation and expansion of tumor-infiltrating lymphocytes (TILs) in increasing the benefit of immunotherapies in patients with solid tumors. We found that intratumoral injection of a tumor-selective oncolytic vaccinia virus encoding interleukin-7 (IL-7) and IL-12 into tumor-bearing immunocompetent mice activated the inflammatory immune status of previously poorly immunogenic tumors and resulted in complete tumor regression, even in distant tumor deposits. Mice achieving complete tumor regression resisted rechallenge with the same tumor cells, suggesting establishment of long-term tumor-specific immune memory. Combining this virotherapy with anti–programmed cell death-1 (PD-1) or anti–cytotoxic T lymphocyte antigen 4 (CTLA4) antibody further increased the antitumor activity as compared to virotherapy alone, in tumor models unresponsive to either of the checkpoint inhibitor monotherapies. These findings suggest that administration of an oncolytic vaccinia virus carrying genes encoding for IL-7 and IL-12 has antitumor activity in both directly injected and distant noninjected tumors through immune status changes rendering tumors sensitive to immune checkpoint blockade. The benefit of intratumoral IL-7 and IL-12 expression was also observed in humanized mice bearing human cancer cells. These data support further investigation in patients with non-inflamed solid tumors.

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