Cancer immunotherapy

Here, we provide a brief overview of the approaches and strategies underlying bacteria-based cancer immunotherapy (BCiT). We also describe and summarize research in the field of synthetic biology, which aims to regulate bacterial growth and gene expression for immunotherapeutic use. Finally, we discuss the current clinical status and limitations of BCiT.

Early detection of immunotherapy-induced tumor response is of major benefit for patients but can be complicated by therapy-induced pseudoprogression. A consensus guideline-iRECIST- was developed as a modification of Response Evaluation Criteria in Solid Tumours (RECIST version 1.1). Here we describe which next steps are required to test its validity and how novel approaches for response criteria might be developed and included.

CAR T cell therapy is an effective cancer treatment, but biological and manufacturing hurdles hamper its broad breakthrough. Although the first step towards automated manufacture of CAR cells has been taken, new technologies are needed to enable the treatment of large patient groups.

Tumor-infiltrating lymphocytes (TILs) are critical in the elimination of cancer cells, a concept highlighted by recent advances in cancer immunotherapy. Significant evidence reveals that their organization in tertiary lymphoid structures together with specific subpopulation composition/balances stimulates cellular crosstalk and anti-tumor immunity in patients.

Recent years have seen rapid advances in the preclinical development and clinical evaluation of oncolytic (cancer-lysing) virus-based therapies, and these are emerging as treatment modality for some cancers. There are challenges to address, however, if we are to maximize the impact of these therapies in patients.

The benefit from immune checkpoint inhibitors is tempered by immunologic toxicities, which involve diverse organs, have varying biology, onset time, and severity. Herein, we identify important areas of controversy and open research questions in the field of immune-related toxicity.

Immunotherapy using immune-checkpoint modulators revolutionizes the oncology field far beyond their remarkable clinical efficacy in some patients. It creates radical changes in the evaluation of treatment efficacy and toxicity with a more holistic vision of the patient with cancer.

Defective immune responses have been reported in cutaneous T-cell lymphoma (CTCL). Here the authors show that in patients with mycosis fungoides, the most common CTCL, malignant T cells upregulate MHC-I as a mechanism to evade NK-mediated immunity.

Response rates to immune-checkpoint inhibitors in patients with advanced sarcoma remain modest. Here the authors report the results of a phase 2 study of durvalumab (anti-PD-L1) in combination with the anti-VEGF receptor tyrosine-kinase inhibitor pazopanib in unselected advanced sarcomas with correlative genomic analysis.

The role of the tumor microenvironment in immunotherapy response in intrahepatic cholangiocarcinoma remains unclear. Here, single cell RNA and TCR sequencing of samples before and after immunotherapy highlights the role of CD8 T-cell status conversion and exhaustion induced by Macro CD5L+ in treatment response.

Mahalingam et al. report findings from a first-in-human dose escalation study of the tumor microenvironment modulator VT1021 in patients with advanced solid tumors. VT1021 is found to be safe and well tolerated and the recommended phase II dose is established based on pharmacokinetic/dynamic properties and preliminary clinical activities.

Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment of hematological cancers, however, immune related adverse effects, such as cytokine release syndrome (CRS) may limit therapeutic success. Here authors show that CRS is preceded by a latent stage, characterized by neutrophil activation and distinct cytokine signatures, and that CAR-T re-expansion might associate with severe CRS.

SECOMBIT was a clinical trial testing different sequences of immunotherapy (ipilimumab plus nivolumab) and targeted therapy (encorafenib plus binimetinib) for untreated BRAF-mutated metastatic melanoma. Here the authors report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy, and preliminary biomarkers evaluation.

Bipolar androgen therapy (BAT) is a treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Here the authors report the results of a phase 2 trial of BAT plus nivolumab (anti-PD1) in patients with advanced mCRPC.

Neoadjuvant treatment represents a therapeutic option for locally advanced gastric cancer (LAGC). Here the authors report the results of a randomized phase 2 trial of camrelizumab (anti-PD1) and apatinib (anti-VEGFR2) combined with nab-paclitaxel plus S-1 versus chemotherapy alone as neoadjuvant treatment for LAGC.

Mimura et al. report findings from a single arm, phase I/II study of combined radiation and anti-PD-1 therapy in patients with advanced or recurrent gastric cancer. Combination therapy achieves a disease control rate of 22.5% for non-irradiated lesions via an abscopal effect, or 40% for irradiated lesions, and a median survival time of 230 days.

Ensenyat–Mendez et al. construct a gene expression-based machine learning classifier to predict the response of triple-negative breast cancer to immune checkpoint inhibition combined with chemotherapy. Predictive performance of the 37-gene classifier is better than that of PD-1 or PD-L1.

Tomlins et al. develop an Immunotherapy Response Score (IRS) to predict clinical benefit from checkpoint inhibition across solid tumors. IRS integrates TMB and gene expression, is evaluable from FFPE material, and is predictive for real-world progression-free survival and overall survival in patients receiving PD-1/PD-L1 blockade therapy.

Xiao, Guo et al. use imaging mass cytometry to evaluate the spatial composition of the tumor microenvironment in melanoma. The authors identify features of the microenvironment associated with response to anti-PD-1 immunotherapy.

Rocconi et al. analyse gene expression data from patients with ovarian cancer receiving the autologous tumor cell immunotherapy gemogenovatucel-T (Vigil) as part of the VITAL study. The authors identify ENTPD1/CD39 expression as a predictor of relapse-free and overall survival benefit.

Recognition of tumour antigen induces dendritic cell activation and migration to the lymph node. Here, the authors use photoconvertible mice to demonstrate that some activated dendritic cells are retained in tumours and gradually lose function, but their ability to support local anti-tumour responses can be augmented by anti-PD-L1 blockade.

Natural killer (NK) cells control tumor growth through direct cytotoxicity and recruitment of other leukocytes. Here, using photoconversion-based labeling to track the fate of NK cells in vivo, the authors demonstrate that loss of NK cell function occurs very rapidly following their entry into tumors, but can be reversed by IL-15 administration.

CD8 + T cells are central players in anti-tumour immunity. Here authors identify Cul5, a ubiquitin E3 ligase as an important inhibitor of CD8 + T cell anti-tumour cytotoxicity and persistence via involvement with both T cell receptor and cytokine-regulated central pathways.

Oncogenic KRAS mutations can dictate the formation of an immune-suppressive tumor microenvironment. Here the authors report that, in KRAS mutant colorectal cancer, the upregulation of circATXN7 in tumor-specific cytotoxic T lymphocytes is associated with increased sensitivity to activation-induced cell death and resistance to immunotherapy.”

Activation of the cGAS-STING pathway has been associated with the promotion of anti-tumor immunity. Here the authors show that TET2 upregulates tumor cGAS to activate STING in endothelial cells, inducing tumor vascular normalization and enhancing efficacy of anti-PD-L1 alone or combined with IL-2 in liver cancer preclinical models.

PD-L1 expression on the surface of cancer cells is believed to contribute to tumor immune evasion via triggering the inhibitory T cell co-receptor, PD-1, resulting in decreased T cell cytotoxicity. Here authors show that OTUB2 regulates PD-L1 expression via inhibition of its ubiquitin-mediated degradation, and that OTUB2 inhibition increases T cell cytotoxicity directed against tumors.

CD3 bispecific antibodies (bsAbs) have demonstrated promising clinical responses in hematological malignancies but clinical benefit in solid tumors has been limited. Here the authors report that pre-treatment vaccination promotes the infiltration of tumor-(un)related effector CD8 T cells, improving the efficacy of CD3 bsAbs in solid tumors.

Modulation of regulatory T cells (Treg) in the tumour environment is a potential avenue to bolster anti-tumor immunity. Here Liu et al show that perturbation of the negative feedback loop involving STAT1- IFITM3 influences anti-tumor immunity, and that IFITM3 or STAT1 deficiency resulting in the fragility of tumor-infiltrating Treg cells.

BCMA-specific CAR T-cell therapies have shown high response rates in multiple myeloma (MM), however the majority of patients still relapse. Here the authors show that CD24-positive MM cells increase after BCMA-CAR-T treatment in patients, and that dual-targeted BCMA/CD24 CAR-T cells can improve anti-tumor efficacy in MM preclinical models.

Clonal Vb2 usage is common among patients with mature T cell lymphoma. Here the authors report the generation of allogeneic CAR-T cells selectively targeting TCR Vb2+ on malignant T cells, with limited normal T cell destruction.

Human natural killer T (NKT) cells have been proposed as a cellular platform for CAR engineering. Here the authors report that IL-12 engineering reprograms CAR-expressing NKT cells to long-lived Th1-polarized cells with potent anti-tumor activity in leukemia and neuroblastoma preclinical models.

Extracellular vesicles (EVs) have been actively explored for diagnostic and therapeutic applications. Here, the authors report a universal metabolic tagging technology to generate chemically tagged EVs from parent cells, modulate EV-cell interactions, and develop potent EV-based cancer vaccines.

Patients with myeloma multiple treated with BCMA CAR T cells often relapse with BCMA-negative disease or antigen escape. Here the authors describe the design of TACI-directed single and dual CAR T cells with in vitro and in vivo activity against multiple myeloma, overcoming BCMA antigen loss.

Vγ9Vδ2 (Vδ2) T cells have been proposed as cell carriers for off-the-shelf CAR therapies. Here the authors describe CD16 as a biomarker for the selection of Vδ2 T cells with high levels of cytotoxicity and report the anti-tumor activity of engineered CD16high Vδ2 T cells in ovarian cancer preclinical models.