The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Basic Tumor Immunology co-Section Editor Dr. Cornelis J.M. Melief.
“Randomized, double-blind, placebo-controlled, global phase III trial of talimogene laherparepvec combined with pembrolizumab for advanced melanoma” by Jason A. Chesney et al
JCO (2023)
Jason A. Chesney et al report a phase III, double-blinded, placebo-controlled, international trial in which 692 patients with stage IIIB-IVM1c unresectable cutaneous melanoma were randomized to receive pembrolizumab in combination with either talimogene laherparepvec (T-VEC) or placebo. Patients were anti-PD-1 naïve and were stratified by disease stage and prior BRAF-targeting therapy. The co-primary endpoints were PFS by modified RECIST 1.1 (BICR) and OS, with key secondary endpoints including PFS by modified Immune-related Response Criteria (irRC)-RECIST (BICR), OS for patients with stage IIIB-IVM1b disease, ORR, DRR, and safety. With a median follow-up of 25.6 months for the primary analysis, median PFS was not significantly improved (overall stratified hazard ratio [HR] 0.86; 95% CI 0.71 to 1.04; p=0.13) despite a numerically higher PFS in the T-VEC versus placebo arm (14.3 vs 8.5 months). This difference remained non-significant even when iPFS was measured by irRC-RECIST. The OS difference was also non-significant between study arms (HR 0.96; 95% CI 0.76 to 1.22; p=0.74), and remained non-significant in an OS sensitivity analysis excluding patients with stage IVM1c disease. The ORR (and complete response rate, CRR) and DRRs were 48.6% (CRR 17.9%) and 42.2% for the T-VEC arm versus 41.3% (CRR 11.6%) and 34.1% for the placebo arm. Immune-related adverse events of any grade occurred in 27.5% and 24.8% of patients in the T-VEC and placebo arms, respectively.
Why this matters: Despite failing to meet its primary progression-free and overall survival endpoints, this trial demonstrated a numerically higher PFS, ORR, CRR, and DRR in the T-VEC arm with comparable safety between arms. Evaluation of T-VEC efficacy in other oncology indications remains important
“CD4+ helper T cells endow cDC1 with cancer-impeding functions in the human tumor micro-environment” by Xin Lei et al
Nature Communications (2022)
Tumor antigen-loaded dendritic cells (DCs) have had limited success in clinical trials thus far. Xin Lei and colleagues show that coculture with CD4+ T cells enables classical type 1 dendritic cells (cDC1s) to induce cytotoxic responses in effector lymphocytes. Compared to the other types of DC cells analyzed, including monocyte-derived DCs and plasmacytoid DCs, only cDC1s cocultured with CD4+ T cells activated gene expression signatures associated with antigen processing and presentation and T cell recruitment. Additionally, CD4+ T cell co-cultured, or ‘helped’ cDC1s induced optimal antigen-specific CD8+ T cell responses, measured through proliferation and Granzyme B production. Interestingly, ‘helped’ cDC1s share a significant portion of gene expression signatures with mature DCs and tumor infiltrating DCs. Using melanoma patient cohorts in The Cancer Genome Atlas, the group found correlations between the ‘helped’ cDC1 gene expression signature and activated CD8+ T cell signatures, longer OS, and importantly, a high predictive value to response to anti-PD-1 blockade.
Why this matters: These data highlight the importance of cDC1 and T helper cell interactions for effective anti-tumor cytotoxic CD8+ T cell immune responses. These insights are important for optimization of DC therapies and for therapeutic cancer vaccine and adoptive T cell transfer strategy. Additionally, the ‘helped’ cDC1 gene signature holds promise as a potential future biomarker for response to anti-PD-(L)1.
“Persistent mutation burden drives sustained anti-tumor immune responses” by Noushin Niknafs et al
Nature Medicine (2022)
Tumor mutational burden (TMB) has historically been recognized as a predictive biomarker for response to immune checkpoint inhibitors (ICIs), presumably due to elevated neoantigen load in tumors with high TMB. However, association between high TMB and clinical benefit with ICIs is highly variable, and in many cancers data are either lacking or show no predictive value. Importantly, overall TMB does not account for mutation/neoantigen loss through chromosomal loss or deletions. Noushin Niknafs and colleagues hypothesized that both mutations in single-copy/haploid regions of the genome, as well as multi-copy mutations, are less likely to be lost through chromosomal loss or deletions, and termed this phenomenon “persistent TMB (pTMB).” In The Cancer Genome Atlas datasets, the occurrence of pTMB was distinct from overall TMB. Across tumor types, pTMB had varying predictability for overall outcomes in treatment-naïve tumors, regardless of treatment type, but pTMB was positively correlated with response to ICIs and a more pro-inflammatory and cytolytic tumor microenvironment. Moreover, any tumor-specific correlations between TMB and clinical outcomes was largely driven by the existence of pTMB.
Why this matters: This study exemplifies why overall TMB has been a suboptimal biomarker for ICI response, and provides evidence for using a more stringent and stable measure of mutational load, such as pTMB. Further prospective validation is needed to establish pTMB as a pan-tumor ICI response biomarker.
“Targeting TBK1 to overcome resistance to cancer immunotherapy” by Yi Sun et al
Nature (2023)
TBK1, a serine/threonine kinase serine/threonine kinase that regulates the activation of interferon regulatory factor 3 (IRF3) in response to pathogens, has previously been identified as a candidate target to enhance susceptibility to PD-1 blockade in genetic screens. Yi Sun et al demonstrate that loss of TBK1 sensitizes tumor cells to effector cytokines and further show that inhibition of TKB1 overcomes resistance to anti-PD-1 in murine models as well as patient-derived organotypic tumor spheroids. Pharmacologic inhibition of TBK1 enhanced anti-tumor efficacy with anti-PD-1 in murine organotypic tumor spheroids derived from tumors with primary and secondary anti-PD-1 resistance as well as in patient-derived organotypic tumor spheroids from melanoma resistant to anti-PD-1 monotherapy or in combination with anti-CTLA-4. In mice, an enrichment for early exhausted/effector CD8+ T cells with a corresponding decrease in terminally exhausted effector T cells, increased cytokine production, and marked myeloid cell expansion was observed with TBK1 inhibition. Strikingly, tumor-specific loss of TKB1 did not result in significant perturbations in infiltrating immune cells. In a CRISPR screen of B16 melanoma cells challenged with tumor necrosis factor alpha (TNFa) and interferon gamma (IFNy), TKB1 was the top hit and the parental line cell viability decreased incrementally with increasing doses of TBK1 inhibitor in combination with TNFa and IFNy—this finding was confirmed in tumor cell intrinsic human melanoma cells lines, PDOTS, and patient-derived organoids. Mechanistically, death of TNFa and IFNy-treated cells lacking TKB1 required RIPK1/RIPK3/pseudokinase MLKL activation, caspase 3 signaling, and JAK-STAT signaling, and was independent of the STING-TBK1-IRF3 cytosolic nucleic acid pathway.
Why this matters: TBK1 inhibition increases tumor sensitivity to cytokine-induced cell death and enhances response to PD-1 blockade, representing a potential strategy to overcome resistance to checkpoint blockade.