Abstract The advent of immunotherapy has made an indelible mark on the field of cancer therapy, especially the application of immune checkpoint inhibitors in clinical practice. Although immunotherapy has proven its efficacy and safety in some tumors, many patients still have innate or acquired resistance to immunotherapy. The emergence of this phenomenon is closely related to the highly heterogeneous immune microenvironment formed by tumor cells after undergoing cancer immunoediting. The process of cancer immunoediting refers to the cooperative interaction between tumor cells and the immune system that involves three phases: elimination, equilibrium, and escape. During these phases, conflicting interactions between the immune system and tumor cells result in the formation of a complex immune microenvironment, which contributes to the acquisition of different levels of immunotherapy resistance in tumor cells. In this review, we summarize the characteristics of different phases of cancer immunoediting and the corresponding therapeutic tools, and we propose normalized therapeutic strategies based on immunophenotyping. The process of cancer immunoediting is retrograded through targeted interventions in different phases of cancer immunoediting, making immunotherapy in the context of precision therapy the most promising therapy to cure cancer. 

/pdf/novel-strategies-for-cancer-immunotherapy-counter-1yhxgo5s.pdf

Novel strategies for cancer immunotherapy: counter-immunoediting therapy

INTRODUCTION
Cervical cancer is the fourth most common cause of cancer-related death worldwide. High-risk locally advanced or recurrent/metastatic cervical cancers have a poor prognosis with routine treatments. The objective of this study is to analyze the data available in the literature on therapies and molecules currently in use to improve the prognosis of recurrent cervical cancer.


AREAS COVERED
An extensive literature search was conducted by authors to identify relevant trials on various databases. Articles in English published until September 2023 that investigate different pharmacotherapy strategies for the treatment of recurrent cervical cancer, were included. Results of various pharmacological regimens including different combinations of chemotherapy, immune checkpoint inhibitors, DNA damage repair inhibitors and antibody-drug conjugates were analyzed.


EXPERT OPINION
In recent years, there have been significant improvements in the outcomes of recurrent/metastatic cervical cancer. However, these improvements do not address the unmet need in terms of oncological outcomes. The introduction of immunotherapy and targeted therapies showed advantages in cervical cancer patients. New therapies and combination strategies must be implemented. Centralization of care and enrollment in clinical trials are of paramount importance. Primary and secondary prevention remains the fundamental goal to reduce the burden of cervical cancer.

Pharmacotherapy for the treatment of recurrent cervical cancer: an update of the literature.

Background Tumor-infiltrating lymphocyte (TIL) therapy has shown efficacy in metastatic melanoma, non-small cell lung cancer, and other solid tumors. Our preclinical work demonstrated more robust CD8 predominant TIL production when agonistic anti-4-1BB and CD3 antibodies were used in early ex vivo TIL culture. Methods Patients with treatment-refractory metastatic colorectal (CRC), pancreatic (PDAC) and ovarian (OVCA) cancers were eligible. Lymphodepleting chemotherapy was followed by infusion of ex vivo expanded TIL, manufactured at MD Anderson Cancer Center with IL-2 and agonistic stimulation of CD3 and 4-1BB (urelumab). Patients received up to six doses of high-dose IL-2 after TIL infusion. Primary endpoint was evaluation of objective response rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 with secondary endpoints including disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), and safety. Results 17 patients underwent TIL harvest and 16 were treated on protocol (NCT03610490), including 8 CRC, 5 PDAC, and 3 OVCA patients. Median age was 57.5 (range 33–70) and 50% were females. Median number of lines of prior therapy was 2 (range 1–8). No responses were observed at 12 weeks. Ten subjects achieved at least one stable disease (SD) assessment for a DCR of 62.5% (95% CI 35.4% to 84.8%). Best response included prolonged SD in a patient with PDAC lasting 17 months. Median PFS and OS across cohorts were 2.53 months (95% CI 1.54 to 4.11) and 18.86 months (95% CI 4.86 to NR), respectively. Grade 3 or higher toxicities attributable to therapy were seen in 14 subjects (87.5%; 95% CI 61.7% to 98.4%). Infusion product analysis showed the presence of effector memory cells with high expression of CD39 irrespective of tumor type and low expression of checkpoint markers. Conclusions TIL manufactured with assistance of 4-1BB and CD3 agonism is feasible and treatment is associated with no new safety signals. While no responses were observed, a significant portion of patients achieved SD suggesting early/partial immunological effect. Further research is required to identify factors associated with resistance and functionally enhance T cells for a more effective therapy.

Efficacy and safety of autologous tumor-infiltrating lymphocytes in recurrent or refractory ovarian cancer, colorectal cancer, and pancreatic ductal adenocarcinoma

BACKGROUND
As an unconventional subpopulation of T lymphocytes, γδ T cells can recognize antigens independently of major histocompatibility complex restrictions. Recent studies have indicated that γδ T cells play contrasting roles in tumor microenvironments-promoting tumor progression in some cancers (eg, gallbladder and leukemia) while suppressing it in others (eg, lung and gastric). γδ T cells are mainly enriched in peripheral mucosal tissues. As the cervix is a mucosa-rich tissue, the role of γδ T cells in cervical cancer warrants further investigation.


METHODS
We employed a multiomics strategy that integrated abundant data from single-cell and bulk transcriptome sequencing, whole exome sequencing, genotyping array, immunohistochemistry, and MRI.


RESULTS
Heterogeneity was observed in the level of γδ T-cell infiltration in cervical cancer tissues, mainly associated with the tumor somatic mutational landscape. Definitely, γδ T cells play a beneficial role in the prognosis of patients with cervical cancer. First, γδ T cells exert direct cytotoxic effects in the tumor microenvironment of cervical cancer through the dynamic evolution of cellular states at both poles. Second, higher levels of γδ T-cell infiltration also shape the microenvironment of immune activation with cancer-suppressive properties. We found that these intricate features can be observed by MRI-based radiomics models to non-invasively assess γδ T-cell proportions in tumor tissues in patients. Importantly, patients with high infiltration levels of γδ T cells may be more amenable to immunotherapies including immune checkpoint inhibitors and autologous tumor-infiltrating lymphocyte therapies, than to chemoradiotherapy.


CONCLUSIONS
γδ T cells play a beneficial role in antitumor immunity in cervical cancer. The abundance of γδ T cells in cervical cancerous tissue is associated with higher response rates to immunotherapy.

Multiomics profiling reveals the benefits of gamma-delta (γδ) T lymphocytes for improving the tumor microenvironment, immunotherapy efficacy and prognosis in cervical cancer.

Simple Summary The systemic treatment of advanced sarcoma remains challenging. Conventional chemotherapy and anti-angiogenic agents, even in the most responsive histologic subtypes, result in short responses and poor clinical outcomes. In a context where new therapeutic approaches are required, several strategies of immunotherapy have emerged as promising options, such as immune checkpoint inhibitors, vaccines, and adoptive cell therapy. In this review, we aim to summarize the current state and challenges of immunotherapy in patients with advanced bone and soft-tissue sarcomas. Abstract There is substantial heterogeneity between different subtypes of sarcoma regarding their biological behavior and microenvironment, which impacts their responsiveness to immunotherapy. Alveolar soft-part sarcoma, synovial sarcoma and undifferentiated pleomorphic sarcoma show higher immunogenicity and better responses to checkpoint inhibitors. Combination strategies adding immunotherapy to chemotherapy and/or tyrosine–kinase inhibitors globally seem superior to single-agent schemes. Therapeutic vaccines and different forms of adoptive cell therapy, mainly engineered TCRs, CAR-T cells and TIL therapy, are emerging as new forms of immunotherapy for advanced solid tumors. Tumor lymphocytic infiltration and other prognostic and predictive biomarkers are under research.

/pdf/current-landscape-of-immunotherapy-for-advanced-sarcoma-qoq3568e.pdf

Current Landscape of Immunotherapy for Advanced Sarcoma

Purpose The safety and objective clinical responses were observed in the phase I study using adjuvant autologous tumor-infiltrating lymphocytes (TILs) following concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients. Methods and materials 156 patients with stage III-IVb and pretreatment EBV DNA (pEBV DNA) levels of ≥4000 copies/mL were randomly assigned to receive CCRT combined with TIL infusion (n=78) or CCRT alone (n=78). All patients received CCRT and patients assigned to the TIL group received TIL infusion within 1 week after CCRT. The primary endpoint was investigator-assessed progression-free survival (PFS) at 3 years. Results After a median follow-up of 62.3 months, no significant difference was observed in the 3-year PFS rate between the CCRT plus TIL infusion group and CCRT alone group (75.6% vs. 74.4%, HR,1.08; 95% CI, 0.62-1.89). TIL infusion was safe without grade 3 or 4 adverse events and all the high-grade adverse effects were associated with myelosuppression caused by CCRT. Exploratory analysis showed that a potential survival benefit was observed with TILs in patients with lower levels of circulating CD8+TIM3+ cells, serum IL-8 or PD-L1. The infused TIL products in patients with favorable outcomes were associated with increased transcription of IFN-γ and a series of inflammatory related genes and a lower exhausted score. Conclusion The primary objective of prolonging PFS with CCRT plus TILs in high-risk NPC patients was not met. These findings may provide evidence for the design of future trials investigating the combination of TILs plus immune checkpoint inhibitors based on CCRT in high-risk NPC patients. Trial registration number NCT02421640 

A phase 2 Randomised Controlled Trial of Adjuvant Tumor-Infiltrating Lymphocytes for Pretreatment Epstein-Barr Virus DNA-selected High-Risk Nasopharyngeal Carcinoma Patients

BACKGROUND Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here, we explored the safety, feasibility, and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous TILs (auto-TILs) following concurrent chemoradiotherapy (CCRT) in patients with CC who had locally advanced disease. METHODS Twenty-seven patients with CC with stage III–IV disease were recruited in this single-center, phase I study. TILs were isolated from lesions in the uterine cervix and generated under good manufacturing practice (GMP) conditions and then infused after CCRT plus i.m. IL-2 injections. RESULTS TILs from 20 of the 27 patients were successfully expanded, with a feasibility of 74.1%. Twelve patients received TILs following CCRT. Adverse events (AEs) were primarily attributable to CCRT. Only 1 (8.3%) patient experienced severe toxicity with a grade 3 hypersensitivity reaction after TIL infusion. No autoimmune AEs, such as pneumonitis, hepatitis, or myocarditis, occurred, and there were no treatment-related mortalities. Nine of 12 patients (75.0%) attained a complete response, with a disease control duration of 9–22 months. Translational investigation showed that the transcriptomic characteristics of the infused TIL products and some immune biomarkers in the tumor microenvironment and serum of patients with CC at baseline were correlated with the clinical response. CONCLUSION TIL-based ACT following CCRT was safe in an academic center setting, with potentially effective responses in patients with locally advanced CC. “Hot” inflammatory immune environments were beneficial to the clinical efficacy of TIL-based ACT as adjuvant therapy. TRIAL REGISTRATION ClinicalTrials.gov NCT04443296. FUNDING National Key R&D Program; Sci-Tech Key Program of the Guangzhou City Science Foundation; the Guangdong Province Sci-Tech International Key Program; the National Natural Science Foundation of China.

http://www.jci.org/articles/view/157726/files/pdf

Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer

Tumor-infiltrated double-negative regulatory T cells predict outcome of T cell-based immunotherapy in nasopharyngeal carcinoma.

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A phase 2 Randomised Controlled Trial of Adjuvant Tumor-Infiltrating Lymphocytes for Pretreatment Epstein-Barr Virus DNA-selected High-Risk Nasopharyngeal Carcinoma Patients

Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer

Tumor-infiltrated double-negative regulatory T cells predict outcome of T cell-based immunotherapy in nasopharyngeal carcinoma.