Case Report: Adequate T and B Cell Responses in a SARS-CoV-2 Infected Patient After Immune Checkpoint Inhibition

After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic

Increasing Costs of Skin Cancer due to Increasing Incidence and Introduction of Pharmaceuticals, 2007-2017

Skin cancer is the most common type of cancer and its incidence is increasing. The objective of this study was to describe the trends in reimbursed drug and hospital costs of benign and (pre)malignant skin tumours, and to present future projections. Therefore, nationwide hospital and drug reimbursement data (for the period 2007–17) were used. In 2017, malignant skin tumours were the 4(th) most costly cancer in the Netherlands (after breast, colorectal, and lung cancer). The total costs for skin tumours increased from €278 million for 384,390 patients (in 2007) to €465 million for 578,355 patients (in 2017). Drug costs increased from €0.7 million to €121 million (over the period 2007–17), resulting in a 26% share of overall costs in 2017. Future costs are projected to reach €1.35 billion in 2030. In conclusion, the increasing costs of skin cancer are strongly affected by the increasing incidence and introduction of expensive drugs, and future projections are for an alarming increase

Granzyme B is correlated with clinical outcome after PD-1 blockade in patients with stage IV non-small-cell lung cancer

BACKGROUND: A minority of patients with advanced non-small-cell lung cancer (NSCLC) benefit from treatment with immune checkpoint inhibitors (ICIs). Ineffective effector function of activated T and NK cells may lead to reduced tumor cell death, even when these activated effector cells are released from their immune checkpoint brake. Hence, in this study we aimed to assess the association of baseline serum granzyme B, as well as germline variation of the GZMB gene, with clinical outcome to programmed cell death protein 1 (PD-1) blockade. METHODS: A total of 347 patients with stage IV NSCLC who started nivolumab treatment between June 2013 and June 2017 were prospectively included. Baseline serum and whole blood was available, allowing for protein quantification and targeted DNA sequencing. Clinical outcome was based on best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors, V.1.1, progression-free survival (PFS), and overall survival (OS). RESULTS: Patients with low serum levels of granzyme B had worse PFS (HR: 1.96; 95% CI: 1.12 to 3.43; p=0.018) and worse OS (HR: 2.08; 95% CI: 1.12 to 3.87; p=0.021) than patients with high baseline serum levels. To validate the findings, germline variation of GZMB rs8192917 was assessed. Patients with homozygous and heterozygous variants of GZMB rs8192917 had worse BOR (OR: 1.60; 95% CI: 1.01 to 2.52; p=0.044) and worse PFS (HR: 1.38; 95% CI:1.02 to 1.87; p=0.036) than wild types. CONCLUSIONS: A low baseline serum level of granzyme B and germline variation of GZMB was associated with worse clinical outcome in NSCLC, emphasizing the relevance and additional value of monitoring germline genetic variations which mirror cytotoxic functions of T cells in ICI therapy. TRAIL REGISTRATION NUMBER: Dutch Trial Registry (NL6828)

Response and survival of metastatic melanoma patients treated with immune checkpoint inhibition for recurrent disease on adjuvant dendritic cell vaccination

Vaccination with autologous dendritic cells (DC) loaded ex vivo with melanoma-associated antigens is currently being tested as an adjuvant treatment modality for resected locoregional metastatic (stage III) melanoma. Based on its mechanism of action, DC vaccination might potentiate the clinical efficacy of concurrent or sequential immune checkpoint inhibition (ICI). The purpose of this study was to determine the efficacy of ICI administered following recurrent disease during, or after, adjuvant DC vaccination. To this end, we retrospectively analyzed clinical responses of 51 melanoma patients with either irresectable stage III or stage IV disease treated with first- or second-line ICI following recurrence on adjuvant DC vaccination. Patients were analyzed according to the form of ICI administered: PD-1 inhibition monotherapy (nivolumab or pembrolizumab), ipilimumab monotherapy or combined treatment with ipilimumab and nivolumab. Treatment with first- or second-line PD-1 inhibition monotherapy after recurrence on adjuvant DC vaccination resulted in a response rate of 52%. In patients treated with ipilimumab monotherapy and ipilimumab-nivolumab response rates were 35% and 75%, respectively. In conclusion, ICI is effective in melanoma patients with recurrent disease on adjuvant DC vaccination

CD45RA(+)CCR7(-) CD8 T cells lacking co-stimulatory receptors demonstrate enhanced frequency in peripheral blood of NSCLC patients responding to nivolumab

Background Checkpoint inhibitors have become standard care of treatment for non-small cell lung cancer (NSCLC), yet only a limited fraction of patients experiences durable clinical benefit, highlighting the need for markers to stratify patient populations. Methods To prospectively identify patients showing response to therapy, we have stained peripheral blood samples of NSCLC patients treated with 2nd line nivolumab (n = 71), as well as healthy controls, with multiplex flow cytometry. By doing so, we enumerated 18 immune cell subsets and assessed expression for 28 T cell markers, which was followed by dimensionality reduction as well as rationale-based analyses. Results In patients with a partial response (PR), representing best overall response (BOR) according to RECIST v1.1, the number of CD8 T cells at baseline and during treatment is similar to those of healthy controls, but 2-fold higher than in patients with progressive and stable disease (PD and SD). CD8 T cell populations in PR patients show enhanced frequencies of T effector memory re-expressing CD45RA (TEMRA) cells, as well as T cells that express markers of terminal differentiatio

Association between single-nucleotide polymorphisms and adverse events in nivolumab-treated non-small cell lung cancer patients

Background: Treatment with PD-1 inhibitors can be hampered by severe auto-immune-related toxicities. Our objective was to identify single-nucleotide polymorphisms (SNPs) in genes previously associated with auto-immunity, which are associated with toxicities in nivolumab-treated NSCLC patients. This was in order to identify patients prone to develop severe toxicities and to gain more insight into the underlying pathobiology. Methods: We analysed 322 nivolumab-treated patients and assessed the association with toxicities for seven SNPs in four genes, which are considered contributors to PD-1-directed T-cell responses, i.e., PDCD1, PTPN11, ZAP70 and IFNG. Every SNP was tested for its association with toxicity endpoints. Significant associations were tested in a validation cohort. Results: A multivariable analysis in the exploration cohort showed that homozygous variant patients for PDCD1 804C>T (rs2227981) had decreased odds for any grade treatment-related toxicities (n = 96; OR 0.4; 95% CI 0.2–1.0; p = 0.039). However, this result could not be validated (n = 85; OR 0.9; 95% CI 0.4–1.9; p = NS). Conclusions: Our results show that it is unlikely that the investigated SNPs have a clinical implication in predicting toxicity. A finding, even though negative, that is considered timely and instructive towards further research in biomarker development for checkpoint inhibitor treatments

Donor-derived cell-free DNA detects kidney transplant rejection during nivolumab treatment

Background: In solid organ transplant (SOT) recipients, transplant rejection during immune checkpoint inhibitor (ICI) treatment for cancer is a clinical problem. Donor-derived cell-free DNA (dd-cfDNA) can be detected in blood and is a sensitive biomarker for diagnosis of acute rejection in SOT recipients. To our best knowledge, this is the first case report of a kidney transplant recipient with advanced cancer treated with ICI who was monitored with dd-cfDNA. Case presentation: A 72-year old female with a long-standing renal transplant was diagnosed with advanced melanoma in 2018 and was treated with the anti-PD1 antibody nivolumab. Within 12 days after the first administration of nivolumab, dd-cfDNA ratio increased to 23%, suggesting allograft rejection. Her kidney transplant function deteriorated and acute rejection was confirmed by renal transplant biopsy. As the rejection could not be controlled despite immunosuppressive treatment, a transplant nephrectomy was necessary and haemodialysis was started. Immunological analysis of the renal explant showed infiltration of alloreactive, nivolumab-saturated, PD1+ cytotoxic T cells. After transplant nephrectomy, she experienced nivolumab-related toxicity and rapid disease progression. Conclusion: Clinicians prescribing ICIs should be aware that SOT recipients are a

The EORTC-DeCOG nomogram adequately predicts outcomes of patients with sentinel node–positive melanoma without the need for completion lymph node dissection

Purpose: Based on recent advances in the management of patients with sentinel node (SN)–positive melanoma, we aimed to develop prediction models for recurrence, distant metastasis (DM) and overall mortality (OM). Methods: The derivation cohort consisted of 1080 patients with SN-positive melanoma from nine European Organization for Research and Treatment of Cancer (EORTC) centres. Prognostic factors for recurrence, DM and OM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across centres. The models were externally validated using a prospective cohort consisting of 705 German patients with SN-positive: 473 trial participants of the German Dermatologic Cooperative Oncology Group study (DeCOG-SLT) and 232 screened patients. A nomogram was developed for graphical presentation. Results: The final model for recurrence and the calibrated models for DM and OM included ulceration, age, SN tumour burden and Breslow thickness. The models showed reasonable calibration. The c-index for the recurrence, DM and OM model was 0.68, 0.70 and 0.70, respectively, and 0.70, 0.72 and 0.74, respectively, in external validation. The EORTC-DeCOG model identified a robust low-risk group, with all identified low-risk patients (approximately 4% of the entire population) having a 5-year recurrence probability of <25% and an overall 5-year recurrence rate of 13%. A model including information on completion lymph node dissection (CLND) showed only marginal improvement in model performance. Conclusions: The EORTC-DeCOG nomogram provides an adequate prognostic tool for patients with SN-positive melanoma, without the need for CLND. It showed consistent results across validation. The nomogram could be used for patient counselling and might aid in adjuvant therapy decision-making