Homologous platelet gel on radiation-induced dermatitis in a patient receiving head and neck radiotherapy plus cetuximab: A case report.

INTRODUCTION: Acute radiodermatitis is a significant complication of cancer radiotherapy, and platelet-based therapies are emerging as potential new treatments. MAIN SYMPTOMS AND IMPORTANT CLINICAL FINDINGS: In this report, we present the case of a patient with head and neck cancer undergoing radiotherapy combined with the monoclonal antibody cetuximab. After 4 weeks of this treatment, the patient developed cutaneous radiation dermatitis. Despite receiving standard treatment with corticosteroids and emollient cream, the lesion did not improve. MAIN DIAGNOSIS: cutaneous radiation dermatitis on head and neck cancer patient. THERAPEUTIC INTERVENTIONS: Topical application of platelet gel was initiated on the wound. From the second week of radiotherapy to the 4th week, homologous platelet-rich plasma was applied on the dermatitis using a bandage, 4 times a day. OUTCOMES: The topical treatment with homologous platelet gel resulted in complete healing of the radiodermatitis, including restoration of the epidermis, reepithelialization, and reduction in associated pain. CONCLUSION: homologous platelet gel might be an alternative to standard treatment of radiation dermatitis.

Systematic vitamin D supplementation is associated with improved outcomes and reduced thyroid adverse events in patients with cancer treated with immune checkpoint inhibitors: results from the prospective PROVIDENCE study.

BACKGROUND: Hypovitaminosis D can have a negative prognostic impact in patients with cancer. Vitamin D has a demonstrated role in T-cell-mediated immune activation. We hypothesized that systematic vitamin D repletion could impact clinical outcomes in patients with cancer receiving immune-checkpoint inhibitors (ICIs). METHODS: We planned a prospective observational study (PROVIDENCE) to assess serum vitamin D levels in patients with advanced cancer receiving ICIs (cohort 1 at treatment initiation, cohort 2 during treatment) and the impact of systematic repletion on survival and toxicity outcomes. In an exploratory analysis, we compared the clinical outcomes of cohort 1 with a control cohort of patients followed at the participating centers who did not receive systematic vitamin D repletion. RESULTS: Overall, 164 patients were prospectively recruited in the PROVIDENCE study. In cohort 1, consisting of 101 patients with 94.1% hypovitaminosis (≤ 30 ng/ml) at baseline, adequate repletion with cholecalciferol was obtained in 70.1% at the three months re-assessment. Cohort 2 consisted of 63 patients assessed for vitamin D at a median time of 3.7 months since immunotherapy initiation, with no patients having adequate levels (> 30 ng/ml). Even in cohort 2, systematic supplementation led to adequate levels in 77.8% of patients at the three months re-assessment. Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS, p = 0.013), time to treatment failure (TTF, p = 0.017), and higher disease control rate (DCR, p = 0.016). The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55, 95%CI: 0.34-0.90) and treatment discontinuation (HR 0.61, 95%CI: 0.40-0.91) for patients from PROVIDENCE cohort 1 in comparison to the control cohort. In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events (irAEs) was higher in the PROVIDENCE cohort 1 compared to the control cohort. Nevertheless, patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16, 95%CI: 0.03-0.85). CONCLUSION: The PROVIDENCE study suggests the potential positive impact of early systematic vitamin D supplementation on outcomes of patients with advanced cancer receiving ICIs and support adequate repletion as a possible prophylaxis for thyroid irAEs.

Real-World Outcomes of Latinx Versus Non-Latinx Patients Treated With First-Line Immunotherapy for Metastatic Renal-Cell Carcinoma.

BACKGROUND: There are limited data regarding the impact of ethnicity among patients receiving immune checkpoint inhibitors. We evaluated real-world outcomes between Latinx and non-Latinx patients with metastatic renal-cell carcinoma (mRCC) treated with first-line nivolumab/ipilimumab within 2 different healthcare settings. METHODS: We performed a retrospective analysis of patients with mRCC who received nivolumab/ipilimumab within the Los Angeles County Department of Health Services (LAC-DHS), a safety-net healthcare system, and the City of Hope Comprehensive Cancer Center (COH), a tertiary oncology center, between January 1, 2015 and December 31, 2021. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method and covariates were adjusted using multivariate Cox proportional hazards regression. RESULTS: Of 94 patients, 40 patients (43%) were Latinx while the remainder were non-Latinx (44 pts [46%] White, 7 pts [7%] Asian, and 3 pts [3%] Other). Fifty (53%) and 44 (47%) patients received their care at COH and LAC-DHS, respectively. Most Latinx patients (95%) were treated at LAC-DHS, and most non-Latinx patients (89%) were treated at COH. Pooled analysis by ethnicity demonstrated significantly shorter PFS in Latinx versus non-Latinx patients (10.1 vs. 25.2 months, hazard ratios [HR] 3.61, 95% CI 1.96-6.66, P ≤ .01). Multivariate analysis revealed a HR of 3.41 (95% CI 1.31-8.84; P = .01). At a median follow-up of 11.0 months, the median OS was not reached in either arm at the time of data cutoff. CONCLUSION: Latinx patients with mRCC had a shorter PFS treated with frontline nivolumab/ipilimumab compared to their non-Latinx counterparts. No difference was observed in OS although these data were immature. Larger studies are needed to further interrogate the social and economic determinants of ethnicity on clinical outcomes in mRCC.

Risk Factors for Immune Checkpoint Inhibitor Immunotherapy Toxicity Among Older Adults with Cancer.

OBJECTIVES: Immune checkpoint inhibitor immunotherapy (IO) is revolutionizing cancer care but can lead to significant toxicity. This study seeks to describe potential risk factors for immune-related adverse events (irAEs) specifically among older adults. MATERIALS AND METHODS: This was a retrospective study at a single academic comprehensive cancer center based on chart review data abstracted by physicians. For patients aged ≥70 years, frequency, type, and grade of irAEs and their association with baseline patient demographics, comorbidities, mobility, and functional status were characterized using bivariate analysis. Based on those results, multivariable logistic regressions were constructed to model the association between these characteristics with any grade and grade 3 or higher irAEs. RESULTS: Data were analyzed for 238 patients aged ≥70 years who received IO for mostly (≥90%) advanced cancer between 2011 and 2018. Thirty-nine percent of older adults experienced an irAE and 13% experienced one that was grade 3 or higher. In the multivariable analysis, depression was associated with an increased incidence of any grade irAE, while decreased life-space mobility was associated with an increased incidence of grade ≥3 irAEs. CONCLUSION: Most characteristics of special interest among older adults, include fall risk, weight loss, cognitive limitations, and hearing loss, were not associated with irAEs in our study. However, decreased life-space mobility and depression are potential risk factors for IO toxicity among older adults with advanced cancer. Interventions designed to evaluate and mitigate modifiable risk factors for treatment-related toxicity are needed, and the results of this study may be useful for guiding those efforts.

[Expertise for management of immune-related adverse events in cancer therapy: Mapping of French practicing]. / Gestion des toxicités induites par les inhibiteurs des points de contrôle immunitaire en oncologie : cartographie des pratiques françaises.

Immune checkpoint inhibitors (ICI) are an increasing proportion of oncology therapies. The oncologist is faced with the managing immune-mediated adverse effects (irAEs), which are sometimes complex, the introduction of ICIs in patients with history of autoimmune diseases, and rechallenging after toxicity. This multidisciplinary care is still uneven. The main objective of this study is to describe the management of this irAES within the university hospitals (UH) with oncology department and comprehensive cancer centers (CCC). We built this study around a survey sent to all UH and CCC in metropolitan France, as well as to all the hospitals authorized to treat cancer in the Nord Pas de Calais region, in order to assess the resources available and the areas of improvement. Multidisciplinary tumor boards dedicated to irAEs were available in 39% of CCCs and UHs, the remaining 61% had a network of specialists. The main problem encountered is the difficulty of bringing together the various specialists. The resources available at the regional level were not well known to the practitioners, who declared that the local resources were insufficient. We have identified five areas for improvement: the generalization of therapeutic education, the strengthening of the city-hospital link, the facilitation of access to specialists who know the specificities of irAE, the sharing of information through pharmacovigilance department and the promotion of further studies.

Benefits of combination therapy with immune checkpoint inhibitors and predictive role of tumour mutation burden in hepatocellular carcinoma: A systematic review and meta-analysis.

OBJECTIVES: To investigate the clinical benefits of combination therapy with immune checkpoint inhibitors (ICIs) and best combination regimen for people with advanced hepatocellular carcinoma (HCC) and to explore the predictive performance of tumour mutation burden (TMB). METHODS: We conducted a systematic literature search to identify clinical trials. Meta-analysis and subgroup analyses were performed to estimate the benefits of combination regimens with PD-1/PD-L1 inhibitors for patients with advanced HCC and compare the effectiveness of PD-1/PD-L1 inhibitors and sorafenib as first-line therapy. Individualized analysis and Kaplan-Meier were used to assess the prognostic value of TMB. RESULTS: A total of 29 studies with 5396 patients were included. ICIs' combination therapy had higher ORR (26 % vs 15 %) and DCR (73 % vs 55 %), longer PFS (5.5 vs 3.1 months) and OS (15.9 vs 12.6 months) compared to monotherapy. Anti-PD-1/PD-L1 agents provided improved ORR, DCR, PFS and OS compared to sorafenib. The overall ORs of ORR and DCR in subgroup analysis were 3.49 (95 % CI 2.36-5.17, p < 0.01) and 1.60 (95 % CI 1.15-2.21, p < 0.01). The overall HRs of PFS and OS were 0.68 (95 % CI 0.48-0.96, p = 0.03) and 0.73 (95 % CI 0.62-0.85, p < 0.01). PD-1/PD-L1 inhibitors plus anti-VEGF agents had an advantage in DCR (0.80 vs 0.48, meta-regression =  - 0.32, P < 0.001), but an equal ORR (0.29 vs 0.26) compared to dual immune checkpoint inhibitors. The total OS in Dua-ICIs were 16.5 months (95 % CI 14.2-18.7), yet not reached in the major studies of ICI plus anti-VEGF regimen. In individualized analysis, the 1-year OS was superior for patients who had high-TMB (>10, mutations/Mb) than moderate-TMB (1-10, mutations/Mb; 28 % vs 15 %, P = 0.025). CONCLUSION: Immune checkpoint inhibitors' combination therapy improved clinical outcomes in the management of advanced hepatocellular carcinoma. However, the overall objective response rate still did not exceed 30%. PD-1/PD-L1 inhibitors plus anti-angiogenic agents and dual immunotherapy provided significantly increased survival over sorafenib, which also pose new challenges for future research, and more appropriate and guided control regimens are required. Also, TMB may be a promising prognostic biomarker for immunotherapy in HCC. However, the validation of prospective and large sample studies is needed.

Clinical, genomic, and transcriptomic correlates of response to immune checkpoint blockade-based therapy in a cohort of patients with angiosarcoma treated at a single center.

BACKGROUND: Angiosarcoma is a histologically and molecularly heterogeneous vascular neoplasm with aggressive clinical behavior. Emerging data suggests that immune checkpoint blockade (ICB) is efficacious against some angiosarcomas, particularly cutaneous angiosarcoma of the head and neck (CHN). METHODS: Patients with histologically confirmed angiosarcoma treated with ICB-based therapy at a comprehensive cancer center were retrospectively identified. Clinical characteristics and the results of targeted exome sequencing, transcriptome sequencing, and immunohistochemistry analyses were examined for correlation with clinical benefit. Durable clinical benefit was defined as a progression-free survival (PFS) of ≥16 weeks. RESULTS: For the 35 patients included in the analyses, median PFS and median overall survival (OS) from the time of first ICB-based treatment were 11.9 (95% CI 7.4 to 31.9) and 42.5 (95% CI 19.6 to 114.2) weeks, respectively. Thirteen patients (37%) had PFS ≥16 weeks. Clinical factors associated with longer PFS and longer OS in multivariate analyses were ICB plus other therapy regimens, CHN disease, and white race. Three of 10 patients with CHN angiosarcoma evaluable for tumor mutational burden (TMB) had a TMB ≥10. Five of six patients with CHN angiosarcoma evaluable for mutational signature analysis had a dominant mutational signature associated with ultraviolet (UV) light. No individual gene or genomic pathway was significantly associated with PFS or OS; neither were TMB or UV signature status. Analyses of whole transcriptomes from nine patient tumor samples found upregulation of angiogenesis, inflammatory response, and KRAS signaling pathways, among others, in patients with PFS ≥16 weeks, as well as higher levels of cytotoxic T cells, dendritic cells, and natural killer cells. Patients with PFS <16 weeks had higher numbers of cancer-associated fibroblasts. Immunohistochemistry findings for 12 patients with baseline samples available suggest that neither PD-L1 expression nor presence of tumor-infiltrating lymphocytes at baseline appears necessary for a response to ICB-based therapy. CONCLUSIONS: ICB-based therapy benefits only a subset of angiosarcoma patients. Patients with CHN angiosarcoma are more likely to have PFS ≥16 weeks, a dominant UV mutational signature, and higher TMB than angiosarcomas arising from other primary sites. However, clinical benefit was seen in other angiosarcomas also and was not restricted to tumors with a high TMB, a dominant UV signature, PD-L1 expression, or presence of tumor infiltrating lymphocytes at baseline.

Immunological and nutritional predictive factors in patients receiving pembrolizumab for the first-line treatment of non-small cell lung cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) have prolonged the survival of patients with various carcinomas, including non-small cell lung cancer (NSCLC), and have caused a paradigm shift in cancer treatment. Although programmed death-ligand 1 (PD-L1) expression in tumor cells is a predictive marker of therapeutic efficacy, additional predictive markers are required. This study aimed to explore the role of immunological and nutritional parameters in the prediction of treatment response. METHODS: Patients diagnosed with NSCLC and treated with pembrolizumab were examined retrospectively. Body weight was measured 4-6 weeks before the start of the first treatment, immediately before treatment, and 4-6 weeks after the start of the first treatment. Progression-free survival (PFS) was defined as the time from the start of pembrolizumab treatment to the last follow-up date or until disease progression. Statistical analyses were performed to confirm the association between various factors and association between these factors and PFS. RESULTS: Thirty-eight patients with advanced NSCLC were included. We observed a significant association of weight loss and PD-L1 expression with PFS in the multivariate analysis. A significant correlation was found between the advanced lung cancer inflammation index and neutrophil-to-lymphocyte ratio. A weight loss of > 5% after the start of treatment was significantly associated with worse PFS. CONCLUSIONS: Weight loss is an important negative prognostic factor in patients with NSCLC receiving immunotherapy. Weight maintenance may be important for good ICI treatment efficacy, and future interventions in cancer cachexia are expected to further enhance the treatment efficacy of ICIs.

Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer.

BACKGROUND: Neoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable non-small-cell lung cancer (NSCLC). In early-phase trials, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase 3 trials are needed to confirm these findings. METHODS: In this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection. The primary end points were event-free survival and pathological complete response (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. Overall survival was a key secondary end point. Safety was assessed in all treated patients. RESULTS: The median event-free survival was 31.6 months (95% confidence interval [CI], 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95% CI, 14.0 to 26.7) with chemotherapy alone (hazard ratio for disease progression, disease recurrence, or death, 0.63; 97.38% CI, 0.43 to 0.91; P = 0.005). The percentage of patients with a pathological complete response was 24.0% (95% CI, 18.0 to 31.0) and 2.2% (95% CI, 0.6 to 5.6), respectively (odds ratio, 13.94; 99% CI, 3.49 to 55.75; P<0.001). Results for event-free survival and pathological complete response across most subgroups favored nivolumab plus chemotherapy over chemotherapy alone. At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI, 0.30 to 1.07) and did not meet the criterion for significance. Of the patients who underwent randomization, 83.2% of those in the nivolumab-plus-chemotherapy group and 75.4% of those in the chemotherapy-alone group underwent surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group. CONCLUSIONS: In patients with resectable NSCLC, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone. The addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or impede the feasibility of surgery. (Funded by Bristol Myers Squibb; CheckMate 816 ClinicalTrials.gov number, NCT02998528.).

The potential role of vitamin C in empowering cancer immunotherapy.

Vitamin C also known as L-ascorbic acid is a nutrient naturally occurring in many fruits and vegetables and widely known for its potent antioxidant activity. Several studies have highlighted the importance of using high dose vitamin C as an adjuvant anti-cancer therapy. Interestingly, it has been shown that vitamin C is able to modulate the anti-cancer immune response and to help to overcome the resistance to immune checkpoints blockade (ICB) drugs such as cytotoxic T-lymphocyte antigen 4 (CLTA-4) and programmed cell death ligand 1 (PD-L1/PD-1) inhibitors. Indeed, it was reported that vitamin C regulates several mechanisms developed by cancer cells to escape T cells immune response and resist ICB. Understanding the role of vitamin C in the anti-tumor immune response will pave the way to the development of novel combination therapies that would enhance the response of cancer patients to ICB immunotherapy. In this review, we discuss the effect of vitamin C on the immune system and its potential role in empowering cancer immunotherapy through its pro-oxidant potential, its ability to modulate epigenetic factors and its capacity to regulate the expression of different cytokines involved in the immune response.

Bevacizumab combined with chemotherapy for ovarian cancer: A protocol for systematic review and meta-analysis.

BACKGROUND: The impact of bevacizumab (an anti-vascular endothelial growth factor therapy) remains uncertain, which has been the focus of studies on the management of ovarian cancer (OC). We performed a protocol for systematic review and meta-analysis to assess the efficacy and safety of bevacizumab combined with chemotherapy in OC. METHODS: The presentation of methods and results in this systematic review was performed according to the evaluation guidelines for health care interventions provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol. This study will use the Cochrane Library, Web of Science, PubMed, Embase, Allied and Complementary Medicine Database, China Biomedical Literature Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and Ongoing Clinical Trials Database. The risk of bias of included studies is estimated by taking into consideration the characteristics including random sequence generation, allocation concealment, blinding of patients, blinding of outcome assessment, completeness of outcome data, selective reporting, and other bias by Cochrane Collaboration's tool. All analyses were performed with Review Manager (RevMan) software, version 5.3. RESULTS: The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. CONCLUSION: Bevacizumab combined with chemotherapy may improve progression-free survival and overall survival in patients with OC.

Hurdles for the wide implementation of photoimmunotherapy.

Near infrared photoimmunotherapy (NIR-PIT) is a molecularly targeted treatment for cancers achieved by injecting a conjugate of IRDye700DX® (IR700), a water-soluble silicon phthalocyanine derivative in the near infrared, and a monoclonal antibody that targets cancer cell antigens. NIR-PIT is a highly specific treatment with few side effects that results in rapid immunogenic cell death. Despite it being a very effective and innovative therapy, there are a few challenges preventing full implementation in clinical practice. These include the limits of near infrared light penetration, selection of targets, concerns about tumor lysis syndrome and drug costs. However, NIR-PIT has been approved by the regulatory authorities in Japan, allowing for exploration of how to mitigate challenges while maximizing the benefits of this treatment modality.

Novel Therapies for Follicular Lymphoma and Other Indolent Non-Hodgkin Lymphomas.

OPINION STATEMENT: When selecting therapy for patients with indolent non-Hodgkin lymphoma (iNHL) including follicular (FL), marginal zone (MZL), small lymphocytic (SLL), and lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM), there are several factors to consider. With a median age around 70 at diagnosis, many patients have accumulated comorbid conditions that may limit treatment options. Although incurable for most, iNHL is a chronic disease with a median overall survival measured in years to decades. This long natural history changes the risk-to-benefit balance with a lower acceptance of toxicity early in the treatment course compared to that of aggressive lymphomas. Despite a recent rapid increase in available therapies, overall progress in iNHL has been slow for several reasons. Initial trials grouped iNHLs together making it challenging to appreciate the differential activity among subtypes. We have not been able to develop prognostic models that maintain validity in the era of chemotherapy-free options. Predictive markers have been elusive and without identified molecular signatures, it is challenging to select and sequence therapy. With these clinical factors in mind, in addition to the heterogeneity among and within iNHLs, I do not have a standard treatment algorithm and feel each patient should have an individualized treatment approach. This review focuses on recent updates and controversies in the management of iNHL with a focus on FL and MZL.

Cutaneous T cell lymphoma.

Primary cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. CTCL subtypes demonstrate a variety of clinical, histological, and molecular features, and can follow an indolent or a very aggressive course. The underlying pathogenetic mechanisms are not yet entirely understood. The pathophysiology of CTCL is complex and a single initiating factor has not yet been identified. Diagnosis is based on clinicopathological correlation and requires an interdisciplinary team. Treatment decision is made based on short-term and long-term goals. Therapy options comprise skin-directed therapies, such as topical steroids or phototherapy, and systemic therapies, such as monoclonal antibodies or chemotherapy. So far, the only curative treatment approach is allogeneic haematopoietic stem cell transplantation. Novel therapies, such as chimeric antigen receptor T cells, monoclonal antibodies or small molecules, are being investigated in clinical trials. Patients with CTCL have reduced quality of life and a lack of effective treatment options. Further research is needed to better identify the underlying mechanisms of CTCL development and course as well as to better tailor treatment strategies to individual patients.

Preclinical and Clinical Characterization of Fibroblast-derived Neuregulin-1 on Trastuzumab and Pertuzumab Activity in HER2-positive Breast Cancer.

PURPOSE: To characterize expression of neuregulin-1 (NRG1), an HER3 ligand, in HER2-positive breast cancer and its relation with the efficacy of trastuzumab with or without pertuzumab. EXPERIMENTAL DESIGN: Characterization of NRG1 expression in tumor cell lines, in tumor specimens, and in cancer-associated fibroblasts (CAFs). Patient-derived CAFs were used to investigate NRG1 impact on the activity of trastuzumab with or without pertuzumab in HER2-positive breast cancer cells. The relationship between NRG1 expression and pathologic response to anti-HER2-based neoadjuvant therapy was assessed in a retrospective patient cohort and in the NeoSphere trial. RESULTS: NRG1 was expressed in HER2-positive breast cancer-derived fibroblasts at significantly higher levels than in cancer cells. NRG1 and the conditioned media (CM) from CAFs phosphorylated HER3 and AKT in cancer cells and mediated trastuzumab resistance. Stable genetic depletion of NRG1 from CAFs overcame trastuzumab resistance. Pertuzumab effectively suppressed trastuzumab resistance mediated by either NRG1 or CAF's CM. NRG1 engaged an epithelial-to-mesenchymal transition that was prevented by trastuzumab and pertuzumab. In clinical samples, stromal and/or tumor cell expression of NRG1 determined by immunohistochemistry was uncommon (13.2%) yet significantly linked with residual disease following trastuzumab-based neoadjuvant therapy. In the NeoSphere trial, the magnitude of the difference of pathologic complete response rates favoring the pertuzumab arm was higher in the NRG1-high group. CONCLUSIONS: CAF-derived NRG1 mediates trastuzumab resistance through HER3/AKT, which might be reverted by pertuzumab. In patients with HER2-positive breast cancer, high expression of NRG1 was associated to poor response to trastuzumab, but not in combination with pertuzumab.

Organoid Platform in Preclinical Investigation of Personalized Immunotherapy Efficacy in Appendiceal Cancer: Feasibility Study.

PURPOSE: Immunotherapy efficacy data on appendiceal cancer from clinical trials does not exist, due to appendiceal cancer incidence of 0.97 per 100,000. The goal of this study was to preclinically explore the application of immunotherapy in treating appendiceal cancer in a personalized organoid model. EXPERIMENTAL DESIGN: Patient tumor organoids (PTO) were fabricated using unsorted tumor cells with and without enrichment with patient-matched immune components derived from peripheral blood leukocytes, spleen, or lymph nodes [immune-enhanced PTOs (iPTO)]. Organoids were cultured for 7 days, followed by treatment with immunotherapy (pembrolizumab, ipilimumab, nivolumab), and assessed for treatment efficacy. RESULTS: Between September 2019 and May 2021, 26 patients were enrolled in the study. Successful testing was conducted in 19 of 26 (73.1%) patients, with 13 of 19 (68.4%) and 6 of 19 (31.6%) patients having low-grade appendiceal (LGA) and high-grade appendiceal (HGA) primaries, respectively. Immunotherapy response, with increased expression of granzyme B and cleaved caspase 3 and decreased expression of CK20 and ATP activity, was exhibited in 4 of 19 (21.1%) pembrolizumab-treated and 2 of 19 (10.5%) nivolumab-treated iPTOs. Post-immunotherapy cellular viability, in responding HGA organoids to pembrolizumab, decreased to less than 15% (P < 0.05). LGA iPTO treatment responses were observed in pembrolizumab and nivolumab, with an 8%-47.4% (P < 0.05) viability compared with controls. Ipilimumab showed no efficacy in the examined cohort. CONCLUSIONS: Immunotherapy shows measurable efficacy in appendiceal cancer organoids. Information derived from immunocompetent organoids may be applied in selecting patients for clinical trial enrollment in rare diseases where preclinical models of disease are lacking.

Loss of CD22 expression and expansion of a CD22dim subpopulation in adults with relapsed/refractory B-lymphoblastic leukaemia after treatment with Inotuzumab-Ozogamicin.

Treatment options for relapsed or refractory B-lymphoblastic leukaemia (r/r B-ALL) are limited and the prognosis of these patients remains dismal, but novel immunotherapeutic options such as the anti-CD22 antibody-drug-conjugate Inotuzumab-Ozogamicin (InO) have improved outcomes in these patients. Flow cytometry is essential to assess antigen-expression prior to treatment initiation of antigen-directed immunotherapies. Here, we present flow cytometric and clinical data of three adult patients with r/r B-ALL who failed treatment with InO associated with reduced or lost antigen-expression. In addition, we present comparative data on two different diagnostic CD22-specific antibody clones that exhibit significant differences in staining intensities.

Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-cancer Agents.

The transferrin receptor 1 (TfR1), also known as cluster of differentiation 71 (CD71), is a type II transmembrane glycoprotein that binds transferrin (Tf) and performs a critical role in cellular iron uptake through the interaction with iron-bound Tf. Iron is required for multiple cellular processes and is essential for DNA synthesis and, thus, cellular proliferation. Due to its central role in cancer cell pathology, malignant cells often overexpress TfR1 and this increased expression can be associated with poor prognosis in different types of cancer. The elevated levels of TfR1 expression on malignant cells, together with its extracellular accessibility, ability to internalize, and central role in cancer cell pathology make this receptor an attractive target for antibody-mediated therapy. The TfR1 can be targeted by antibodies for cancer therapy in two distinct ways: (1) indirectly through the use of antibodies conjugated to anti-cancer agents that are internalized by receptor-mediated endocytosis or (2) directly through the use of antibodies that disrupt the function of the receptor and/or induce Fc effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC). Although TfR1 has been used extensively as a target for antibody-mediated cancer therapy over the years, interest continues to increase for both targeting the receptor for delivery purposes and for its use as direct anti-cancer agents. This review focuses on the developments in the use of antibodies targeting TfR1 as direct anti-tumor agents.

Resistance mechanisms to checkpoint inhibitors.

Although multiple immune checkpoint inhibitors (ICI) have been identified and tested in the clinic, antibodies blocking the PD-1/PD-L1 axis have produced the greatest impact on cancer treatment. Many potential mechanisms of treatment failure have been proposed from pre-clinical animal and human translational studies. Pre-clinical studies and clinical trials are underway to better understand how resistance arises and to develop strategies that can circumvent these resistance mechanisms and sensitize patients to anti-PD1/PD-L1 to improve clinical outcomes.

Importance of antibody isotypes in antitumor immunity by monocytes and complement using human-immune tumor models.

Monoclonal antibodies (mAbs) have revolutionized clinical medicine, especially in the field of cancer immunotherapy. The challenge now is to improve the response rates, as immunotherapy still fails for many patients. Strategies to enhance tumor cell death is a fundamental aim, but relevant model systems for human tumor immunology are lacking. Herein, we have developed a preclinical human immune - three-dimensional (3D) tumor model (spheroids) to map the efficiency of tumor-specific isotypes for improved tumor cell killing. Different anti-CD20 Rituximab (RTX) isotypes alone or in combination, were evaluated for mediating complement-dependent cytotoxicity and antibody-dependent phagocytosis by human monocytic cells in 3D spheroids, in parallel with monolayer cultures, of human CD20+ B-cell lymphomas. We demonstrate that the IgG3 variant of RTX has the greatest tumoricidal effect over other isotypes, and when combined with apoptosis-inducing RTX-IgG2 isotype the therapeutic effect can be substantially enhanced. The results show further that the treatment outcome by RTX isotypes is influenced by tumor morphology and expression of the complement inhibitor CD59. Hence, the human immune-3D tumor model is a clinical relevant and attractive ex vivo system to predict mAbs for best efficacy in cancer immunotherapy.