Indication-specific tumor evolution and its impact on neoantigen targeting and biomarkers for individualized cancer immunotherapies

BackgroundIndividualized neoantigen-specific immunotherapy (iNeST) requires robustly expressed clonal neoantigens for efficacy, but tumor mutational heterogeneity, loss of neoantigen expression, and variable tissue sampling present challenges. It is assumed that clonal neoantigens are preferred targets for immunotherapy, but the distributions of clonal neoantigens are not well characterized across cancer types.MethodsWe combined multiregion sequencing (MR-seq) analysis of five untreated, synchronously sampled metastatic solid tumors with re-analysis of published MR-seq data from 103 patients in order to characterize their globally clonal neoantigen content and factors that would impact neoantigen targeting.ResultsBranching evolution in colorectal cancer and renal cell carcinoma led to fewer clonal neoantigens and to clade-specific neoantigens (those shared across a subset of tumor regions but not fully clonal), with the latter not being readily distinguishable in single tumor samples. In colorectal, renal, and bladder cancer, most tumors had few globally clonal neoantigens. Prioritizing mutations with higher purity-adjusted and ploidy-adjusted variant allele frequency enriched for globally clonal neoantigens (those found in all tumor regions), whereas estimated cancer cell fraction derived from clustering-based tools, surprisingly, did not. Neoantigen quality was associated with loss of neoantigen expression in the bladder cancer case, and HLA-allele loss was observed in the renal and non-small cell lung cancer cases.ConclusionsWe show that tumor type, multilesion sampling, neoantigen expression, and HLA allele retention are important factors for iNeST targeting and patient selection, and may also be important factors to consider in the development of biomarker strategies.

Indication-specific tumor evolution and its impact on neoantigen targeting and biomarkers for individualized cancer immunotherapies

Individualized neoantigen specific immunotherapy (iNeST) requires robustly expressed clonal neoantigens for efficacy, but tumor mutational heterogeneity, loss of neoantigen expression, and variable tissue sampling present challenges. To characterize these potential obstacles, we combined multi-region sequencing (MR-seq) analysis of five untreated, synchronously sampled metastatic solid tumors with re-analysis of published MR-seq data from 103 patients. Branching evolution in colorectal cancer and renal cell carcinoma led to fewer clonal neoantigens and to clade-specific neoantigens (those shared across a subset of tumor regions but not fully clonal), with the latter not being readily distinguishable in single tumor samples. Prioritizing mutations with higher purity- and ploidy-adjusted variant allele frequency enriched for globally clonal neoantigens (those found in all tumor regions), whereas estimated cancer cell fraction derived from clustering-based tools, surprisingly, did not. Neoantigen quality was associated with loss of neoantigen expression in the bladder cancer case, and HLA-allele loss was observed in the renal and non-small cell lung cancer cases. Our results show that indication type, multi-lesion sampling, neoantigen expression, and HLA allele retention are important factors for iNeST targeting and patient selection.

Fulminant hepatitis B: A case report

Introduction: Fulminant hepatitis is a severe acute liver disease. It occurs due to massive necrosis of hepatocytes. The disease progresses to lethal outcome within a few days. The most common causes of this disease are toxic substances, autoimmune and viral hepatitis. The aim of the study was to present a lethal case of fulminant hepatitis caused by hepatitis B virus in a patient with treated bladder cancer. Case Outline: A 63-year-old patient was admitted for treatment due to weakness, nausea and decreased diuresis. She had surgery to remove her bladder, which was affected by a malignant process, two years earlier. On admission, she had a subicteric, orderly auscultatory finding. The abdomen was palpably painful below the right costal arch, without organomegaly. The ureterostomy was functional. The diagnosis of acute HBV infection was made by evidence of HBsAg, HBeAg and antiHBc IgM antibody titer. Laboratory findings indicated an increase in transaminases, urea, creatinine, total and conjugated bilirubin, decreased albumin values and coagulation disorders. The patient was treated with hepatoprotective therapy, antibiotics and antiviral therapy. Hemodialysis was performed as needed. Encephalopathy developed on the third day with further progression.The disease progressed with gastrointestinal bleeding and cardiac disorders and ended in death on the ninth day. Conclusion: Fulminant liver damage caused by hepatitis B virus is a severe disease that can be complicated by acute renal failure. The prognosis of the disease is often unfavorable, so optimal treatment requires a liver transplant.

Bladder Condyloma Acuminatum, A Case Report

Background: Human Papilloma virus (HPV) infection is a high incidence entity in the world population. It is highly related to cervical carcinoma, as well as anogenital carcinoma, among others. The presences of bladder HPV lesions are infrequent and there is an association between it and the development of bladder cancer. Case presentation: We present a case of bladder HPV in a woman with a cervical carcinoma history that was presented clinically as a single episode of gross hematuria. We performed a cystoscopy and Holmium laser enucleation of the bladder tumors. Conclusion: We highlight the importance of consider HPV as a differential diagnosis of a bladder tumor, mainly in patients with history of pathologies related with the virus.