JITC’s Reading List – July 2019

July 2019

The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC’s Editor-in-Chief, Dr. Pedro J. Romero. 

“Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity,” by Laurent Gauthier et al.

Cell 2019

Although most immunomodulatory therapeutic approaches to date have focused on enhancing T cell responses, natural killer (NK) cells have also demonstrated robust anti-tumor immune responses through expression of several activating receptors with anti-tumor effector potential. Gauthier et al. reports on the design, production, and characterization of a new generation of trifunctional NK-cell engagers (NKCEs) consisting of mAb fragments targeting the activating NK-cell receptor NKp46 to promote antibody-dependent cell-mediated cytotoxicity (ADCC) via the activating receptor CD16 expressed on NK cells. Results presented here demonstrate that trifunctional NKCEs targeting CD19, CD20, or EGFR as tumor antigens triggered tumor killing by human primary NK cells in vitro. In pre-clinical mouse models of both invasive and solid tumors, NKCEs induced NK-cell accumulation in tumors and were more potent than standard mAbs, rituximab and obinituzumab without off-target effects. These results support the clinical development of NKCEs for next-generation cancer immunotherapy.

“Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial,” by Howard West et al.  

Lancet Oncology 2019

Atezolizumab (mAb against PD-L1) is currently approved for second-line treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) previously treated with chemotherapy based on data demonstrating anticancer immunity and enhanced overall survival (OS).  Based on the hypothesis that combining atezolizumab with chemotherapy would elicit synergistic anticancer immunity through the release of potentially immunogenic tumor antigens, West et al. assessed the efficacy and safety of atezolizumab plus chemotherapy (carboplatin plus nab-paclitaxel) versus chemotherapy alone as first-line treatment for chemotherapy naïve patients with stage IV non-squamous NSCLC and no ALK or EGFR mutations in the IMpower130 phase 3 randomized study. IMpower130 demonstrated a significant and clinically meaningful improvement in OS and a significant improvement in progression-free survival with atezolizumab plus chemotherapy compared with chemotherapy alone as first-line treatment of metastatic NSCLC.

“Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results from the Phase II KEYNOTE-158 Study,” by Hyun Cheol Chung et al.
Journal of Clinical Oncology 2019

KEYNOTE-158 is a phase II basket clinical study investigating the antitumor activity and safety of pembrolizumab in multiple types of advanced solid tumors that have received one or more lines of chemotherapy for recurrent or metastatic disease. This study reports on interim data from patients with previously treated advanced cervical cancer. Results presented by Chung et al. show that pembrolizumab monotherapy demonstrated durable antitumor activity and a manageable safety profile. Of the 98 patients treated, ORR was 12.2% including 3 complete and 9 partial responses, with all responders having PD-L1-positive tumors. Based on these results, the US Food and Drug Administration granted accelerated approval of pembrolizumab for patients with advanced PD-L1–positive cervical cancer who experienced progression during or after chemotherapy.

 “TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion,” by Omar Khan et al.
Nature 2019

T cell exhaustion is a common feature of antigen specific CD8 T cells in various chronic infections and cancers. T cell exhaustion is a chief target of checkpoint blockade in patients with cancer. Recent studies [1-4] and epigenetic analyses have revealed that exhausted T cells (T_ex) differ from effector or memory T cells (T_eff) and (T_mem) by approximately 6,000 open chromatin regions, which is similar to the differences between other major haematopoietic lineages. T_ex cells are therefore not simply a state of activation of T_eff or T_mem cells, but rather a distinct cell type. However, the mechanisms by which the transcriptional and epigenetic development of T_ex cells occurs remain unknown. Khan et al. identify the HMG-box transcription factor TOX as the key inducer of canonical features of T cell exhaustion. Induced by calcineurin and NFAT2, TOX functions as a central regulator of T_ex through initiation of early epigenetic events, implicating the potential benefit of reprogramming T_ex cells for novel therapeutic opportunities. Other virtually synchronous independent publications [1-4] come to remarkably similar conclusions.

1. Yao, C., et al., Single-cell RNA-seq reveals TOX as a key regulator of CD8(+) T cell persistence in chronic infection. Nat Immunol, 2019. 20(7): p. 890-901.
2. Seo, H., et al., TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8(+) T cell exhaustion. Proc Natl Acad Sci U S A, 2019. 116(25): p. 12410-12415.
3. Scott, A.C., et al., TOX is a critical regulator of tumour-specific T cell differentiation. Nature, 2019.
4. Alfei, F., et al., TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature, 2019.