Project description:With the advent of checkpoint blockade therapies, immunotherapy is now a critical modality for the treatment of some cancers. While some patients respond well to checkpoint blockade, many do not, necessitating the need for other forms of therapy. Vaccination against malignancy has been a long sought goal of science. For cancers holding a microbial etiology, vaccination has been highly effective in reducing the incidence of disease. However, vaccination against established malignancy has been largely disappointing. In this review, we discuss efforts to develop diverse vaccine modalities in the treatment of cancer with a particular focus on melanoma. Recent work has suggested that vaccines targeting patient-specific tumor mutations may be more relevant than those targeting unmutated proteins. Nonetheless, tumor cells utilize many strategies to evade host immunity. It is likely that the full potential of cancer vaccination will only be realized when vaccines are combined with other therapies targeting tumor immunoevasive mechanisms. By modulating inhibitory molecules, regulatory immune cells, and the metabolic resources and demands of T cells, scientists and clinicians can ensure vaccine-stimulated T cells are fully functional within the immunosuppressive tumor microevironment.
Project description:BackgroundThe prevalence and cancer-specific death rate of lung cancer (LC) have risen in recent decades. A universally applicable prognostic signature for both adenocarcinoma LC (LUAD) and squamous cell carcinoma LC (LUSC) is still lacking.MethodsA total of 453 patients from The Cancer Genome Atlas (TCGA)-LUAD cohort and 452 patients from TCGA-LUSC cohort were enrolled, and a prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) regression analysis based on the consensus prognostic genes in both cohorts. The newly defined pan-lung cancer risk count (PLCRC) of each patient was calculated via the summation formula.ResultsA total of 23 genes were selected for the calculation of the PLCRC. The PLCRC showed a moderate prognostic value in the entire (p < 0.001, HR: 2.75, AUC: 0.643), LUAD (p < 0.001, HR: 2.51, AUC: 0.636) and LUSC (p < 0.001, HR: 2.89, AUC: 0.656) cohorts. The PLCRC was an independent prognostic factor after adjusting the clinical features. The PLCRC was also effective in nine external validation cohorts and in patients with different clinical features. Activation of extracellular matrix pathways and infiltration of immunocytes promoted the tumorigenesis and development of both LUAD and LUSC. We generated a universally applicable prognostic signature, the PLCRC, which could dichotomize patients with significantly different clinical outcomes and guide the clinical treatment of LC patients. Chemotherapy is more suitable for patients with a low PLCRC, while anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy is more suitable for patients with a high PLCRC.ConclusionWe established and validated a newly defined prognostic signature, the PLCRC, for both LUAD and LUSC patients and provided clinical strategies for patients from different risk subgroups.
Project description:Programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitor has become one of the important treatment options for patients with advanced non-small cell lung cancer (NSCLC). However, only a small subset of patients with NSCLC can currently receive single-agent PD-1 inhibitors as first-line therapy, for the limitations of population selection exclude most patients from immuno-oncology (IO) monotherapy. In order to expand the candidate population for IO first-line treatment and make more newly diagnosed patients benefit from IO treatment, a series of studies are focusing on the combination of IO and other drugs in NSCLC. We reviewed the latest clinical data of IO first-line combination therapy in recent years, suggesting that on the basis of PD-1/PD-L1 inhibitors, combined with other IO, chemotherapy, anti-angiogenic drugs, targeted therapy or radiotherapy may produce synergistic anti-tumor effects. It is expected to benefit more newly diagnosed patients.?.
Project description:Small cell lung cancer (SCLC), an aggressive and devastating malignancy, is characterized by rapid growth and early metastasis. Although most patients respond to first-line chemotherapy, the majority of patients rapidly relapse and have a relatively poor prognosis. Fortunately, immunotherapy, mainly including antibodies that target the cytotoxic T lymphocyte antigen-4 (CTLA-4), checkpoints programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) to block immune regulatory checkpoints on tumor cells, immune cells, fibroblasts cells and endothelial cells, has achieved the milestone in several solid tumors, such as melanoma and non-small-cell lung carcinomas (NSCLC). In recent years, immunotherapy has made progress in the treatment of patients with SCLC, while its response rate is relatively low to monotherapy. Interestingly, the combination of immunotherapy with other therapy, such as chemotherapy, radiotherapy, and targeted therapy, preliminarily achieve greater therapeutic effects for treating SCLC. Combining different immunotherapy drugs may act synergistically because of the complementary effects of the two immune checkpoint pathways (CTLA-4 and PD-1/PD-L1 pathways). The incorporation of chemoradiotherapy in immunotherapy may augment antitumor immune responses because chemoradiotherapy can enhance tumor cell immunogenicity by rapidly inducing tumor lysis and releasing tumor antigens. In addition, since immunotherapy drugs and the molecular targets drugs act on different targets and cells, the combination of these drugs may achieve greater therapeutic effects in the treatment of SCLC. In this review, we focused on the completed and ongoing trials of the combination therapy for immunotherapy of SCLC to find out the rational combination strategies which may improve the outcomes for SCLC.
Project description:Immune checkpoint inhibitors enhance the activation and antitumor activity of the immune system, resulting in durable response rates in a select group of patients. Cytotoxic T lymphocyte antigen 4 (CTLA4) inhibitors target the inhibitory interaction between CTLA4 and CD80 or CD86. Programmed death 1 (PD1) inhibitors target the interaction between PD1 receptors on T-cells and PD-ligand 1 (PD-L1) and PD-ligand 2, blocking the inhibitory signaling and resulting in activation of T-cell effector function. These therapeutic drugs were originally evaluated in patients with metastatic melanoma before expansion to all tumor types, including non-small cell lung cancer (NSCLC) with promising results. The PD1 inhibitors such as pembrolizumab have now received FDA approval in the first-line setting for patients with positive PD-L1 expression tumor types; however, only a portion of patients have shown objective and sustainable responses. To expand the number of patients with observed response to immunotherapeutic agents including patients with negative PD-L1 expression tumors, clinical trials are ongoing to assess the safety and efficacy of combination immune checkpoint inhibitors and combination immune checkpoint inhibitors with targeted therapy. Immune checkpoint inhibitors have been found to be a promising therapeutic drug class with sustainable response rates and a tolerable safety profile, and efforts continue to improve these drugs in patients with NSCLC.
Project description:BACKGROUND Metaplastic breast cancer (MPBC) is a rare subtype of breast cancer that is difficult to manage and is resistant to therapy. Immunotherapy is becoming a promising option for care of several types of cancers including triple negative breast cancer. CASE REPORT We present a case of a patient with chemo-refractory metastatic metaplastic-type of breast cancer with failures to 3 active lines of chemotherapy. The patient achieved a complete and sustained response to chemo-immunotherapy combination with acceptable tolerability and minimal adverse events. The treatment was a combination of anti-PD-L1 antibody (durvalumab) immunotherapy in combination with the chemotherapeutic agent, paclitaxel. CONCLUSIONS This is the first case reporting the successful use of durvalumab and paclitaxel combination for treatment of triple negative breast cancer in general, and in metastatic MPBC in specific.
Project description:Non-small cell lung cancer accounts for approximately 80-85% of all lung cancers and at present represents the main cause of cancer death among both men and women. To date, surgery represents the cornerstone; nevertheless, around 40% of completely resected patients develop disease recurrence. Therefore, combining neoadjuvant chemo-immunotherapy and surgery might lead to improved survival. Immunotherapy is normally well tolerated, although significant adverse reactions have been reported in certain patients treated with inhibitors of immune checkpoints. In this review, we explore the current literature on the use of neoadjuvant chemo-immunotherapy followed by surgery for treatment of locally advanced non-small-cell lung cancer, with particular attention to the histological aspects, ongoing trials, and the most common surgical approaches. In conclusion, neoadjuvant immunotherapy whether combined or not with chemotherapy reveals a promising survival benefit for patients with advanced non-small-cell lung cancer; nevertheless, more data remain necessary to identify the best candidates for neoadjuvant regimens.
Project description:BackgroundThe efficacy of neoadjuvant chemo-immunotherapy (NAT) in esophageal squamous cell carcinoma (ESCC) is challenged by the intricate interplay within the tumor microenvironment (TME). Unveiling the immune landscape of ESCC in the context of NAT could shed light on heterogeneity and optimize therapeutic strategies for patients.MethodsWe analyzed single cells from 22 baseline and 24 post-NAT treatment samples of stage II/III ESCC patients to explore the association between the immune landscape and pathological response to neoadjuvant anti-PD-1 combination therapy, including pathological complete response (pCR), major pathological response (MPR), and incomplete pathological response (IPR).ResultsSingle-cell profiling identified 14 major cell subsets of cancer, immune, and stromal cells. Trajectory analysis unveiled an interesting link between cancer cell differentiation and pathological response to NAT. ESCC tumors enriched with less differentiated cancer cells exhibited a potentially favorable pathological response to NAT, while tumors enriched with clusters of more differentiated cancer cells may resist treatment. Deconvolution of transcriptomes in pre-treatment tumors identified gene signatures in response to NAT contributed by specific immune cell populations. Upregulated genes associated with better pathological responses in CD8 + effector T cells primarily involved interferon-gamma (IFNγ) signaling, neutrophil degranulation, and negative regulation of the T cell apoptotic process, whereas downregulated genes were dominated by those in the immune response-activating cell surface receptor signaling pathway. Natural killer cells in pre-treatment tumors from pCR patients showed a similar upregulation of gene expression in response to IFNγ but a downregulation of genes in the neutrophil-mediated immunity pathways. A decreased cellular contexture of regulatory T cells in ESCC TME indicated a potentially favorable pathological response to NAT. Cell-cell communication analysis revealed extensive interactions between CCL5 and its receptor CCR5 in various immune cells of baseline pCR tumors. Immune checkpoint interaction pairs, including CTLA4-CD86, TIGIT-PVR, LGALS9-HAVCR2, and TNFSF4-TNFRSF4, might serve as additional therapeutic targets for ICI therapy in ESCC.ConclusionsThis pioneering study unveiled an intriguing association between cancer cell differentiation and pathological response in esophageal cancer patients, revealing distinct subgroups of tumors for which neoadjuvant chemo-immunotherapy might be effective. We also delineated the immune landscape of ESCC tumors in the context of clinical response to NAT, which provides clinical insights for better understanding how patients respond to the treatment and further identifying novel therapeutic targets for ESCC patients in the future.
Project description:Non-small-cell lung cancer (NSCLC) causes significant mortality each year. After successful resection of disease stage IB (>4 cm) to IIIA (per AJCC 7), adjuvant platinum-based chemotherapy improves median overall survival and is the standard of care, but many patients still experience recurrence of disease. An adjuvant regimen with greater efficacy could substantially improve outcomes. Pembrolizumab, a programmed cell death-1 inhibitor, has become an important option in the treatment of metastatic NSCLC. ALCHEMIST is a clinical trial platform of the National Cancer Institute that includes biomarker analysis for resected NSCLC and supports therapeutic trials including A081801 (ACCIO), a three-arm study that will evaluate both concurrent chemotherapy plus pembrolizumab and sequential chemotherapy followed by pembrolizumab to standard of care adjuvant platinum-based chemotherapy. Clinical trial registration: NCT04267848 (ClinicalTrials.gov).