Second- and third-generation drugs for immuno-oncology treatment—The more the better?

Dempke, Wolfram; Fenchel, Klaus; Uciechowski, Peter; Dale, Stephen

doi:10.1016/j.ejca.2017.01.001

Cited by 204 publications

(165 citation statements)

References 75 publications

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“…Based on five trials (KEYNOTE-016, KEYNOTE-164, KEYNOTE-012, KEYNOTE-028, and KEYNOTE-158), pembrolizumab has been approved by the FDA for MSI-H or deficient MMR solid tumors. In preliminary studies, a new generation of immunotherapy drugs is being evaluated for downregulating immunosuppressive pathways (for example, VISTA, an immunosuppressive molecule expressed on regulatory T cells, and indoleamine 2,3-dioxygenase (IDO), an enzyme leading to decreased tryptophan level which then suppresses T-cell proliferation) or stimulating immune tumor response (for example, inducible T-cell co-stimulator [ICOS] agonists) 90 .…”

Section: Immunotherapymentioning

confidence: 99%

Recent advances in the management of gastric adenocarcinoma patients

et al. 2018

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Gastric adenocarcinoma (GAC) is one of the most aggressive malignancies and has a dismal prognosis. Therefore, multimodality therapies to include surgery, chemotherapy, targeted therapy, immunotherapy, and radiation therapy are needed to provide advantage. For locally advanced GAC (>cT1B), the emerging strategies have included preoperative chemotherapy, postoperative adjuvant chemotherapy, and (occasionally) postoperative chemoradiation in various regions. Several novel therapies have been assessed in clinical trials, but only trastuzumab and ramucirumab (alone and in combination with paclitaxel) have shown overall survival advantage. Pembrolizumab has been approved by the US Food and Drug Administration on the basis of response rate only for patients with microsatellite instability (MSI-H) or if PD-L1 expression is positive (≥1% labeling index in tumor/immune cells in the presence of at least 100 tumor cells in the specimen). Nivolumab has been approved in Japan on the basis of a randomized trial showing significant survival advantage for patients who received nivolumab compared with placebo in the third or later lines of therapy. The cure rate of patients with localized GAC in the West is only about 40% and that for metastatic cancer is very poor (only 2–3%). At this stage, much more target discovery is needed through molecular profiling. Personalized therapy of patients with GAC remains a challenge.

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Section: Immunotherapymentioning

confidence: 99%

Recent advances in the management of gastric adenocarcinoma patients

et al. 2018

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“…Tumor-Infiltrating Lymphocytes in the TILGen Study Breast Care 2018;13:8-14 13 This limitation has been overcome e.g. by engineered adenoviruses, which are capable of safely vaccinating and re-vaccinating against hundreds of neoepitopes and tumor-associated antigens despite pre-existing immunity against adenovirus [47].…”

Section: Discussionmentioning

confidence: 99%

“…In order to further facilitate this immunogenic potential and to minimize the systemic burdens of chemotherapies, targeted immunotherapies have been the focus of current research programs [12]. Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1), its ligands (PD-L1 and PD-L2), the cytotoxic T-lymphocyte antigen-4 (CTLA-4), or indoleamine-pyrrole-2,3-dioxygenase (IDO) are Food and Drug Administration(FDA)-approved drugs for various cancer types (e.g., breast and lung cancer or melanoma) [12][13][14][15][16]. PD-1 and PD-L1 are physiologically expressed on immunocompetent cells including T cells and are overexpressed on TILs and breast cancer cells [17].…”

Section: Introductionmentioning

confidence: 99%

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes

et al. 2018

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Background: Despite advancements in the treatment of primary and metastatic breast cancer, many patients lack a durable response to these treatments. Patients with triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2(HER2)-positive breast cancer who do not have a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a very poor prognosis. Tumor-infiltrating lymphocytes (TILs) have been identified as a predictive marker for pCR after NACT in TNBC and HER2-positive breast cancer. These patient populations could also be suitable for novel treatment strategies including neoepitope-based therapies. This work analyses the effect of TILs on the pCR in neoadjuvantly treated patients in the TILGen study and presents the procedures aimed at establishing neoepitope-based therapies in this study. Methods: Neoadjuvantly treated HER2-positive and TNBC patients were eligible for the presented analysis concerning the association between TILs and pCR. A total of 146 patients could be identified within the TILGen study. TILs were evaluated as percentage of stromal tumor tissue in core biopsies at primary diagnosis. The phenotype ‘lymphocyte-predominant breast cancer' (LPBC) was associated with pCR by logistic regression adjusted for estrogen receptor status, progesterone receptor status, HER2 status, age at diagnosis, and grading. Results: LPBC was seen in 24 (16.4%) patients. In this patient group, 66.7% achieved a pCR, while the pCR rate was 32.8% in patients with a low TIL count. The adjusted odds ratio was 6.60 (95% confidence interval 2.02-21.56; p < 0.01). Conclusion: TILs are a strong predictor of pCR in TNBC and HER2-positive breast cancer patients. Implications for the use of this information including the effect on prognosis might help to identify patients most likely to benefit from a neoepitope-based therapy approach.

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“…This idea led to development of a series of new inhibitors and new targets: TIM 3, VISTA, LAG-3, IDO-1, KIR, B40, GITR, OX40L, CD137 and ICOS. All these targets, such as molecules, antigenes, receptors etc., take part in immune checkpoints and are under active development for treating oncological pathologies including metastatic RCC (Dempke et al 2017).…”

Section: Patients Taking Interferon Alpha Have Problems With Depresmentioning

confidence: 99%

Renal cell carcinoma drug and cell therapy: today and tomorrow

Pushkin¹,

Burda²,

Sevast’yanov³

et al. 2018

RRP

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Today, considerable progress in the renal cell carcinoma (RCC) treatment has been made due to development of targeted and immunotherapeutic approaches to the RCC treatment, especially in metastasising carcinoma. In the early stages of RCC, it is possible to use partial or total surgical nephrectomy, but in metastases development, the range of efficient treatment methods is dramatically limited. Appearance of targeted drugs like PD-1 and CTLA-4 receptors and their ligands' inhibitors in clinical practice has significantly increased the total survival rate of patients with renal cell carcinoma. Emergence of adoptive cell therapy has opened new possibilities and prospects in RCC treatment. Previously activated in vitro cells are used there, which provides antineoplastic activity. For example, it could be antigen-specific cytotoxic T-lymphocytes (CTL), lymphokine-activated natural killers (LAK-NK-cells) and tumour-infiltrating lymphocytes (TILs). In this review, the authors specified the main molecular markers, associated with RCC; and signalling pathways (VEGFR-and EGFR-signalling pathway), which directly take part in carcinogenesis. The paper also looks at clinically applicable targeted immune drugs and the principle of their effect on tumorous cells. Besides, modern clinical studies of cell drugs have been considered. At the moment, there are a number of variants of targeted and immune drugs for the metastatic RCC treatment. Patients have no opportunity to use all the available agents because of their cost and toxicity level. For the most efficient treatment of patients with diagnosed metastatic RCC, it is necessarily to carry out risk stratification and prognostic factors for the response to treatment.

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Second- and third-generation drugs for immuno-oncology treatment—The more the better?

Cited by 204 publications

References 75 publications

Recent advances in the management of gastric adenocarcinoma patients

Recent advances in the management of gastric adenocarcinoma patients

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes

Renal cell carcinoma drug and cell therapy: today and tomorrow

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