<div>Abstract<p>Immunotherapy with checkpoint inhibitors has changed the paradigm of treatment for many tumors, and endometrial carcinoma is not an exception. Approved treatment options are pembrolizumab or dostarlimab for mismatch repair deficient tumors, pembrolizumab for tumors with high mutational load, and, more recently, pembrolizumab/lenvatinib for all patients with endometrial cancer. Endometrial cancer is a heterogeneous disease with distinct molecular subtypes and different prognoses. Differences between molecular subgroups regarding antigenicity and immunogenicity should be relevant to develop more tailored immunotherapeutic approaches. In this review, we aim to summarize and discuss the current evidence—<i>Facts</i>, and future opportunities—<i>Hopes</i>—of immunotherapy for endometrial cancer, focusing on relevant molecular and tumor microenvironment features of The Cancer Genome Atlas endometrial cancer subtypes.</p></div>
Induction chemotherapy (ICT) followed by definitive treatment is an accepted non-surgical approach for locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, ICT remains a challenge for cisplatin-unfit patients. We evaluated paclitaxel and cetuximab (P-C) as ICT in a cohort of LA-HNSCC patients unfit for cisplatin.This is a retrospective analysis of patients with newly diagnosed LA-HNSCC considered unfit for cisplatin-based chemotherapy (age >70 and/or ECOG≥2 and/or comorbidities) treated with weekly P-C followed by definitive radiotherapy and cetuximab (RT-C) between 2010 and 2017. Toxicity and objective response rate (ORR) to ICT and RT-C were collected. Median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Cox regression analysis was performed to determine baseline predictors of OS and PFS.A total of 57 patients were included. Grade 3-4 toxicity rate to ICT was 54.4%, and there was a death deemed treatment-related (G5). P-C achieved an ORR of 66.7%, including 12.3% of complete responses (CR). After P-C, 45 patients (78.9%) continued with concomitant RT-C. Twenty-six patients (45.6%) achieved a CR after definitive treatment. With a median follow-up of 21.7 months (range 1.2-94.6), median OS and PFS were 22.9 months and 10.7 months, respectively. The estimated 2-year OS and PFS rates were 48.9% and 33.7%, respectively. Disease stage had a negative impact on OS (stage IVb vs. III-IVa: HR = 2.55 [1.08-6.04], p = 0.03), with a trend towards worse PFS (HR = 1.92 [0.91-4.05], p = 0.09). Primary tumor in the larynx was associated with improved PFS but not OS (HR = 0.45 [0.22-0.92], p = 0.03, and HR = 0.69 [0.32-1.54], p = 0.37, respectively).P-C was a well-tolerated and active ICT regimen in this cohort of LA-HNSCC patients unfit for cisplatin-based chemotherapy. P-C might represent a valid ICT option for unfit patients and may aid patient selection for definitive treatment.
Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2 null Il2rγ null SIRPα NOD (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of “responding” patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis.
<div>Abstract<p>Immunotherapy with checkpoint inhibitors has changed the paradigm of treatment for many tumors, and endometrial carcinoma is not an exception. Approved treatment options are pembrolizumab or dostarlimab for mismatch repair deficient tumors, pembrolizumab for tumors with high mutational load, and, more recently, pembrolizumab/lenvatinib for all patients with endometrial cancer. Endometrial cancer is a heterogeneous disease with distinct molecular subtypes and different prognoses. Differences between molecular subgroups regarding antigenicity and immunogenicity should be relevant to develop more tailored immunotherapeutic approaches. In this review, we aim to summarize and discuss the current evidence—<i>Facts</i>, and future opportunities—<i>Hopes</i>—of immunotherapy for endometrial cancer, focusing on relevant molecular and tumor microenvironment features of The Cancer Genome Atlas endometrial cancer subtypes.</p></div>
Reversing the immunosuppressive nature of the tumor microenvironment is critical for the successful treatment of cancers with immunotherapy drugs. Murine cancer models are extremely limited in their diversity and suffer from poor translation to the clinic. To serve as a more physiological preclinical model for immunotherapy studies, this protocol has been developed to evaluate the treatment of human tumors in a mouse reconstituted with a human immune system. This unique protocol demonstrates the development of human immune system (HIS, "humanized") mice, followed by implantation of a human tumor, either a cell-line derived xenograft (CDX) or a patient derived xenograft (PDX). HIS mice are generated by injecting CD34+ human hematopoietic stem cells isolated from umbilical cord blood into neonatal BRGS (BALB/c Rag2-/- IL2RγC-/- NODSIRPα) highly immunodeficient mice that are also capable of accepting a xenogeneic tumor. The importance of the kinetics and characteristics of the human immune system development and tumor implantation is emphasized. Finally, an in-depth evaluation of the tumor microenvironment using flow cytometry is described. In numerous studies using this protocol, it was found that the tumor microenvironment of individual tumors is recapitulated in HIS-PDX mice; "hot" tumors exhibit large immune infiltration while "cold" tumors do not. This model serves as a testing ground for combination immunotherapies for a wide range of human tumors and represents an important tool in the quest for personalized medicine.
Multiple lines of evidence are indicating that cancer development and malignant progression are not exclusively epithelial cancer cell-autonomous processes but may also depend on crosstalk with the surrounding tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are abundantly represented in the TME and are continuously interacting with cancer cells. CAFs are regulating key mechanisms during progression to metastasis and response to treatment by enhancing cancer cells survival and aggressiveness. The latest advances in CAFs biology are pointing to CAFs-secreted factors as druggable targets and companion tools for cancer diagnosis and prognosis. Especially, extensive research conducted in the recent years has underscored the potential of several cytokines as actionable biomarkers that are currently evaluated in the clinical setting. In this review, we explore the current understanding of CAFs secretome determinants and functions to discuss their clinical implication in oncology.
Modeled CA-125 ELIMination rate constant K (KELIM) during neoadjuvant chemotherapy (NACT) predicts survival of advanced ovarian cancer (AOC) patients. The objective of this study is to validate KELIM score in a real-world data cohort of AOC and evaluate its impact on IDS performance, treatment response and survival.
Methodology
Single-centre retrospective study including FIGO III-IV ovarian carcinoma patients treated with NACT between 2015–2020. KELIM score was calculated using Neo-Ca125 validated calculator in Biomarker KineticsTM website. Patients were classified by KELIM score into favourable (≥1) or unfavourable (<1) prognosis; variables were compared between groups using Student-t-test for continuous and χ2 for categorical variables. Progression free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier method and compared by log-rank test. An ordinal logistic regression was performed to identify predictors of CRS.
Results
105 patients were included, 40 in unfavourable and 60 in favourable group. No differences between KELIM groups were observed by age (p=0.08), PS (p=0.25), histologic subtype (p=0.07), FIGO (p=0.78), BRCA status (p=0.80) and maintenance therapy (p=0.80). The majority received CBDCA-paclitaxel (87%, p=0.25). Favourable KELIM was associated with radiological response to NACT (p=0.004), less cycles of NACT (4 vs 4.5, p=0.04), less time to surgery (15.6 vs 17 weeks, p=0.03), IDS performance (p<0.001), complete resection (R0, p=0.046) and better CRS (p=0.02). With a median follow-up of 31 [13–42] months (m), favourable KELIM predicted better OS (49.6 vs 24.6 m, HR 0.38 [CI95% 0.15–0.97], p=0.001) and a trend for better PFS (13.3 vs 11.3m, HR 0.84 [CI95% 0.37–1.93, p 0.07]) was observed.
Conclusion
Neoadjuvant KELIM was associated with radiological response, IDS performance feasibility, better CRS to NACT and was an independent prognostic factor of OS in this cohort. KELIM score may be a valuable clinical tool to guide NACT in AOC.
Introduction: Colorectal cancer (CRC) is the third most common cancer worldwide. It is mostly diagnosed in elderly people, with a median age at diagnosis of 70 years. The aim of our study is to explore whether G8 questionnaire may be helpful to decide the best treatment for older colorectal cancer patients. Methods: From October 2015 to June 2017, we prospectively screened 137 ≥75-years-old patients diagnosed with CRC who were referred for chemotherapy. In our center, these patients underwent oncogeriatric screening for a comprehensive geriatric assessment. Screening is positive in ≥ 85-years-old patients or 75-85-years-old patients with 2 of the following criteria: G8 scale,14, Pfeiffer test >2, Barthel index <90 and positive TIRS social risk scale. In addition, age, comorbidity and ECOG performance status were taken into account for final treatment decision. We hypothesize G8 vulnerability score correlates with toxicity and may help guiding treatment decisions. Results: The median age of screened patients was 80.44 years (75.1-88.9). The most frequent diagnosis was colon cancer (71.8%) followed by rectal cancer (28.2%). 47.4% of patients had metastatic disease. G8 detected vulnerability (<14 score) in 62% of patients. Chemotherapy was more frequently dismissed in these fragile patients (45.9% of G8<14 patients vs 28.6 of G8≥14 patients). Overall, 67 patients received chemotherapy (capecitabine 70.1%, FOLFOX 19.4%, FOLFIRI 1.5%, clinical trial treatment 9%). Interestingly, for those patients who initiated treatment at full-dose intensity, a dose reduction was needed afterwards in 76% of G8<14 patients vs 28.6% of G8≥14 patients (p = 0.032). Tolerance of chemotherapy also significantly differed, with any grade 3/4 toxicity seen in 50% vs 20% of patients respectively (p = 0.041), and a higher risk ratio of presenting such toxicity for G8<14 patients (Risk ratio 4, 95% CI 0.995-16.074). Definitive interruption of treatment due to toxicity was needed in 15.2% vs 6.7% of patients respectively (p = 0.43). There were no toxic deaths. Conclusion: G8<14 score correlates with a greater probability of presenting relevant toxicity. In addition, G8 questionnaire identifies a group of patients who more likely need dose-reduction during treatment. For this reason, G8 appears to be a helpful screening tool for treatment decision-making in elderly colorectal cancer patients.
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