Alejandro A Schaffer

National Institutes of Health | NIH · Center for Cancer Research

Tailoring optimal treatment for individual cancer patients remains a significant challenge. To address this issue, we developed PERCEPTION (PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology), a precision oncology computational pipeline. Our approach uses publicly available matched bulk and single-cell (sc) expression pro...

The advancement of chimeric antigen receptor (CAR) T-cell therapy has been groundbreaking in the treatment of hematological malignancies. However, its application in solid tumors is constrained by antigen variability and unintended off-tumor, on-target toxicities. Addressing these issues, we introduce a genetic algorithm to analyze single-cell tran...

Base editing encompasses techniques that efficiently alter specific nucleotides at the DNA or RNA level. Initially explored for inherited diseases, these techniques hold promise for addressing various genetically driven disorders caused by single nucleotide variants (SNVs). The precise programmability of base editors (BEs) for specific sequences al...

Identifying sex differences in outcomes and toxicity between males and females in oncology clinical trials is important and has also been mandated by National Institutes of Health policies. Here we analyze the Trialtrove database, finding that, strikingly, only 472/89,221 oncology clinical trials (0.5%) had curated post-treatment sex comparisons. A...

Bispecific antibodies have emerged as promising candidates for cancer treatment, prompting the necessity for a comprehensive understanding of their potential efficacy and toxicity across various cancer types. Leveraging single cell sequencing data, we systematically evaluated the efficacy and toxicity of all cell surface gene pairs across multiple...

In the era of precision medicine, performing comparative analysis over diverse patient populations is a fundamental step toward tailoring healthcare interventions. However, the critical aspect of equitably selecting molecular features across multiple patients is often overlooked. To address this challenge, we introduce FALAFL (FAir muLti-sAmple Fea...

Introduction: Gliomas, including aggressive forms such as glioblastoma (GBM) and lower-grade gliomas (LGG), present formidable challenges for treatment. Since the late 1980’s it has been known that loss of chromosome 10 (10 loss) and gain of chromosome 7 (7 gain) often co-occur in GBM. The reasons for this frequently co-occurring event are not very...

The aging of the immune system has profound implications for individual immune responses, yet precise quantification of immune age remains a challenge. Analyzing single-cell peripheral blood mononuclear cells (PBMC) transcriptomics data from 981 healthy individuals, we developed IMMClock (IMMune Clock), a human immune age clock derived from single...

In the era of precision medicine, performing comparative analysis over diverse patient populations is a fundamental step towards tailoring healthcare interventions. However, the critical aspect of equitably selecting molecular features across multiple patients is often overlooked. To address this challenge, we introduce FALAFL (FAir muLti-sAmple Fe...

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intra-tumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we applied spatially resolved transcriptomics...

The co-occurrence of chromosome 10 loss and chromosome 7 gain in gliomas is the most frequent loss-gain co-aneuploidy pair in human cancers, a phenomenon that has been investigated without resolution since the late 1980s. Expanding beyond previous gene-centric studies, we investigate the co-occurrence in a genome-wide manner taking an evolutionary...

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant efficacy in treating hematological cancers but faces challenges in treating solid tumors due to antigen heterogeneity and off-tumor, on-target expression in normal tissues. To combat these challenges, we developed a novel genetic algorithm approach to analyze patient tumor...

Decreased intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, even highly homogenous tumors may display variability in their aggressiveness, and how immunologic-factors impinge on their aggressiveness remains understudied. Here we studied the mechanisms responsible for the immune-escape of...

Simple Summary A major barrier to success for chimeric antigen receptor (CAR) T-cell therapies in solid tumors is selecting optimal target antigens. Target antigens should be uniformly expressed by cancer cells and minimally so by healthy tissues in the body. Analyzing single-cell RNA-sequencing data of patient tumors and of healthy tissue referenc...

Introduction Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymatic disorder that is particularly prevalent in Africa, Asia, and the Middle East. This study aimed to assess the long-term health risks associated with G6PD deficiency. Methods A retrospective cohort study was conducted using data from a national healthcare provi...

Recent studies exploring the impact of methylation in tumor evolution suggest that while the methylation status of many of the CpG sites are preserved across distinct lineages, others are altered as the cancer progresses. Since changes in methylation status of a CpG site may be retained in mitosis, they could be used to infer the progression histor...

Identifying patients that are likely to respond to cancer immunotherapy is an important, yet highly challenging clinical need. Using 3139 patients across 17 different cancer types, we comprehensively studied the ability of two common copy-number alteration (CNA) scores—the tumor aneuploidy score (AS) and the fraction of genome single nucleotide pol...

e18808 Background: NIH guidance advises clinical trials to analyze participants by sex to improve inclusivity. We performed a systematic analysis of reported differences in outcomes between males and females in a registry of oncology clinical trials to characterize treatment response differences more broadly by sex for future trials. Methods: We an...

Background: Gingivobuccal complex oral squamous cell carcinoma (GBC-OSCC) is an aggressive malignancy with high mortality often preceded by premalignant lesions, including leukoplakia. Previous studies have reported genomic drivers in OSCC, but much remains to be elucidated about DNA methylation patterns across different stages of oral carcinogene...

Chimeric antigen receptor T (CAR-T) cell therapies have revolutionized cancer treatment. While CAR-T has yielded tremendous clinical success for patients with liquid tumors, its potential remains to be unleashed against solid tumors. One key challenge is identifying optimal targets for these therapies: cell surface proteins that are expressed highl...

Recent studies exploring the impact of methylation in tumor evolution suggest that while the methylation status of many of the CpG sites are preserved across distinct lineages, others are altered as the cancer progresses. Since changes in methylation status of a CpG site may be retained in mitosis, they could be used to infer the progression histor...

Background: Precision oncology is gradually advancing into mainstream clinical practice, demonstrating significant survival benefits. However, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. Methods: We present ENLIGHT, a transcriptomics-based computational approach that identifies clinically r...

Background: Synthetic lethality (SL) denotes a genetic interaction between two genes whose co-inactivation is detrimental to cells. Since the seminal paper of Hartwell and colleagues has raised the possibility that SL can be used to devise highly selective cancer treatments, it has been one of the promising approaches for precision oncology and dru...

Small cell lung carcinoma (SCLC) is prototypical of cancers with exceptional chemoresistance, and metastatic capabilities fueled by remarkable heterogeneity. The cell-extrinsic factors that govern SCLC heterogeneity are poorly understood especially since non-genetic mechanisms are thought to be major contributors to its intratumoral heterogeneity a...

BACKGROUND Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive enzymatic disorder, particularly prevalent in Africa, Asia and the Middle East. In the US, about 14% of black men are affected. Individuals with G6PD deficiency are often asymptomatic but may develop hemolysis following an infection or upon consumption of specif...

Identifying patients with low tumor mutation burden (TMB) that are likely to respond to cancer immunotherapy is an important, yet highly challenging clinical need. Using 3,139 patients across 17 different cancer types, we comprehensively studied the ability of two common copy number alteration (CNA) scores – the tumor aneuploidy score (AS) and the...

About 15% of human cancer cases are attributed to viral infections. To date, virus expression in tumor tissues has been mostly studied by aligning tumor RNA sequencing reads to databases of known viruses. To allow identification of divergent viruses and rapid characterization of the tumor virome, we develop viRNAtrap, an alignment-free pipeline to...

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder involving interactions between different cell types in the brain. Previous single-cell and bulk expression Alzheimer's studies have reported conflicting findings about the key cell types and cellular pathways whose expression is primarily altered in this disease. We re-analyzed...

Nonalcoholic steatohepatitis (NASH)-induced hepatocellular carcinoma (HCC) and its precursor, nonalcoholic fatty liver disease (NAFLD) are an unmet health issue due to widespread obesity. We assessed copy number changes of genes associated with hepatocarcinogenesis and oxidative pathways at a single-cell level. Eleven patients with NASH-HCC and 11...

Various studies have shown that high tumor mutation burden (TMB) may predict response to immune checkpoint therapy, at least in some cancer types. However, identifying patients with low TMB that are still likely to respond to cancer immunotherapy is an important open challenge. Recently, Spurr et al. reported that the tumor aneuploidy score (AS), d...

Background Precision oncology is gradually advancing into mainstream clinical practice, demonstrating significant survival benefits. However, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. Methods We present ENLIGHT, a transcriptomics-based computational approach that identifies clinically re...

Cancer occurs more frequently in men while autoimmune diseases (AIDs) occur more frequently in women. To explore whether these sex biases have a common basis, we collected 167 AID incidence studies from many countries for tissues that have both a cancer type and an AID that arise from that tissue. Analyzing a total of 182 country-specific, tissue-m...

Importance The recent successes of poly-ADP ribose polymerase (PARP) inhibitors and belzutifan support germline genetic data as an exciting, accessible source for biomarkers in cancer treatment. This study hypothesizes, however, that most oncology clinical trials using germline data largely prioritize BRCA1/2 as biomarkers and PARP inhibitors as th...

Sex is an important factor that influences disease development, progression, and treatment. In multiple non-reproductive cancers, sex differences in incidence, progression, treatment response, survival, and other clinical outcomes are observed. Overall, males have a 20% higher chance of developing cancer over their lifetime, and experience worse cl...

Computational identification and quantification of distinct microbes from high throughput sequencing data is crucial for our understanding of human health. Existing methods either use accurate but computationally expensive alignment-based approaches or less accurate but computationally fast alignment-free approaches, which often fail to correctly a...

About 15% of human cancer cases are attributed to viral infections. To date, virus expression in tumor tissues has been mostly studied by aligning tumor RNA sequencing reads to databases of known viruses. To allow identification of divergent viruses and rapid characterization of the tumor virome, we developed viRNAtrap, an alignment-free pipeline t...

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder involving interactions between different cell types in the brain. Previous single-cell and bulk expression Alzheimer’s studies have reported conflicting findings about the key cell types and cellular pathways whose expression is primarily altered in this disease. We reanalyze thes...

About 15% of human cancer cases are attributed to viral infections. To date, virus expression in tumor tissues has been mostly studied by aligning tumor RNA sequencing reads to databases of known viruses. To allow identification of divergent viruses and rapid characterization of the tumor virome, we developed viRNAtrap, an alignment-free pipeline t...

Vaccines have allowed for a significant decrease in COVID-19 risk, and new antiviral medications can prevent disease progression if given early in the course of the disease. The rapid and accurate estimation of the risk of severe disease in new patients is needed to prioritize the treatment of high-risk patients and maximize lives saved. We used el...

Cancer occurs more frequently in men while autoimmune diseases (AIDs) occur more frequently in women. To explore whether these sex biases have a common basis, we collected 170 AID incidence studies from many countries for tissues that have both a cancer type and an AID that arise from that tissue. Analyzing a total of 182 country-specific, tissue-m...

Despite recent reports of microbes living within tumor cells, the identification of intracellular microbes remains an open and important challenge. Here we introduce CSI-Microbes (computational identification of Cell type Specific Intracellular Microbes), a computational approach for the discovery of cell-type specific intracellular microbial taxa...

A combination treatment designed to target the multiple clones of a patient’s tumor could decrease the likelihood of resistant emergence. The ability to learn and predict the response of a drug at a single-cell resolution could help to design such optimal combinations. A lack of large-scale patients’ datasets with single-cell (sc) expression hinder...

Chimeric antigen receptor (CAR) T cell therapy is a powerful and promising tool for unleashing lasting antitumor immunity, which is currently studied in numerous blood and solid cancers. Here, mining single cell transcriptomics datasets of solid tumors, we survey many existing CAR targets, aiming to identify new solid tumor types in which these tar...

e20540 Background: Tailoring the best treatments to cancer patients is an important open challenge. Here, we build a precision oncology data science and software framework for PERsonalized single-Cell Expression-based Planning for Treatments In Oncology (PERCEPTION). Methods: Our approach capitalizes on recently published matched bulk and single-ce...

Tailoring the best treatments for individual cancer patients is an important open challenge. Here, we build a precision oncology computational pipeline for PERsonalized single-Cell Expression-based Planning for Treatments In ONcology (PERCEPTION). Our approach capitalizes on recently published matched bulk and single-cell (SC) transcriptome profile...

Background: Immune protection following either vaccination or infection with SARS-CoV-2 decreases over time. Objective: We aim to describe clinical and sociodemographic characteristics associated with COVID-19 infection at least 14 days after booster vaccination in the Israeli population. Methods: We conducted a population-based study among ad...

The FDA has recently approved a high tumor mutational burden (TMB-high) biomarker, defined by ≥10 mutations/Mb, for the treatment of solid tumors with pembrolizumab, an immune checkpoint inhibitor (ICI) that targets PD1. However, recent studies have shown that this TMB-high biomarker is only able to stratify ICI responders in a subset of cancer typ...

Mining a large cohort of single-cell transcriptomics data, here we employ combinatorial optimization techniques to chart the landscape of optimal combination therapies in cancer. We assume that each individual therapy can target any one of 1269 genes encoding cell surface receptors, which may be targets of CAR-T, conjugated antibodies or coated nan...

Background Precision oncology is gradually advancing into mainstream clinical practice, demonstrating significant survival benefits. However, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. Methods We present ENLIGHT, a transcriptomics-based computational approach that identifies clinically re...

Tailoring the best treatments to cancer patients is an important open challenge. Here, we build a precision oncology data science and software framework for PERsonalized single-Cell Expression-based Planning for Treatments In Oncology (PERCEPTION). Our approach capitalizes on recently published matched bulk and single-cell transcriptome profiles of...

The tumor microenvironment (TME) is a complex mixture of cell types whose interactions affect tumor growth and clinical outcome. To discover such interactions, we developed CODEFACS (COnfident DEconvolution For All Cell Subsets), a tool deconvolving cell type-specific gene expression in each sample from bulk expression, and LIRICS (Ligand-Receptor...

Background Vaccines are highly effective in preventing severe disease and death from COVID-19, and new medications that can reduce severity of disease have been approved. However, many countries are facing limited supply of vaccine doses and medications. A model estimating the probabilities for hospitalization and mortality according to individual...

The FDA has recently approved a high tumor mutational burden (TMB-High, defined by ≥10 mutations/Mb) as a biomarker for the treatment of advanced solid tumors with pembrolizumab, an immune checkpoint inhibitor (ICI) that targets PD1. However, recent studies have shown that this TMB-high biomarker is only able to stratify ICI responders in a subset...

Immune protection following either vaccination or infection with SARS-CoV-2 is thought to decrease over time. We designed a retrospective study, conducted at Leumit Health Services in Israel, to determine the kinetics of SARS-CoV-2 IgG antibodies following administration of two doses of BNT162b2 vaccine, or SARS-CoV-2 infection in unvaccinated indi...

The availability of single-cell transcriptomics data opens new opportunities for rational design of combination cancer treatments in a systematic manner. Mining such data, we employed combinatorial optimization techniques to explore the landscape of optimal combination therapies in solid tumors, including brain, head and neck, melanoma, lung, breas...

Objectives To determine whether time elapsed since the second injection of the Pfizer-BioNTech BNT162b2 mRNA vaccine was significantly associated with the risk of covid-19 infection after vaccination in people who received two vaccine injections. Design Test negative design study. Setting Electronic health records of a large state mandated health...

Background Engineered versions of adeno-associated virus (AAV) are commonly used in gene therapy but evidence revealing a potential oncogenic role of natural AAV in hepatocellular carcinoma (HCC) has raised concerns. The frequency of potentially oncogenic integrations has been reported in only a few populations. AAV infection and host genome integr...

The availability of single-cell transcriptomics data opens new opportunities for rational design of combination cancer treatments. Mining such data, we employed combinatorial optimization techniques to explore the landscape of optimal combination therapies in solid tumors including brain, head and neck, melanoma, lung, breast and colon cancers. We...

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapies have yielded transformative clinical success for patients with blood tumors, but their full potential remains to be unleashed against solid tumors. One challenge is finding selective targets: cell surface proteins that are expressed widely by cancer cells and minimally by healthy cells in...

Cancer occurs more frequently in men while autoimmune diseases (AIDs) occur more frequently in women. To explore whether these sex biases have a common basis, we collected 170 AID incidence studies from many countries for tissues that have both a cancer type and an AID that arise from that tissue. Analyzing a total of 182 country-specific, tissue-m...

Background: Immune protection following either vaccination or infection with SARS-CoV-2 decreases over time. Objective: To determine the kinetics of SARS-CoV-2 IgG antibodies following administration of two doses of BNT162b2 vaccine, or SARS-CoV-2 infection in unvaccinated individuals. Methods: Antibody titers were measured between January 31, 2021...

Background The DNA sequences encoding ribosomal RNA genes (rRNAs) are commonly used as markers to identify species, including in metagenomics samples that may combine many organismal communities. The 16S small subunit ribosomal RNA (SSU rRNA) gene is typically used to identify bacterial and archaeal species. The nuclear 18S SSU rRNA gene, and 28S l...

Importance: Israel was among the first countries to launch a large-scale COVID-19 vaccination campaign, and quickly vaccinated its population, achieving early control over the spread of the virus. However, the number of COVID-19 cases is now rapidly increasing, which may indicate that vaccine protection decreases over time. Objective: To determine...

Objective: Hepatocellular carcinoma (HCC) represents a typical inflammation-associated cancer. Tissue resident innate lymphoid cells (ILCs) have been suggested to control tumour surveillance. Here, we studied how the local cytokine milieu controls ILCs in HCC. Design: We performed bulk RNA sequencing of HCC tissue as well as flow cytometry and s...

Background Until coronavirus disease 2019 (COVID-19) drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Toward this objective, we conducted a large population study in Clalit Health Services (CHS), the largest healthcar...

Motivation: Computational reconstruction of clonal evolution in cancers has become a crucial tool for understanding how tumors initiate and progress and how this process varies across patients. The field still struggles, however, with special challenges of applying phylogenetic methods to cancers, such as the prevalence and importance of copy numb...

Motivation and research question: The U.S. Food and Drug Administration recently approved treatment with pembrolizumab, an immune checkpoint inhibitor (ICI) targeting PD1 (anti-PD1), for all advanced solid tumors with high tumor mutational burden (TMB), defined as ≥10 mutations/Megabase (mut/Mb). Recent studies have suggested that strength of immun...

The availability of single-cell transcriptomics data opens new opportunities for rational design of combination cancer treatments in a systematic manner. Mining such data, we explore the landscape of optimal combination therapy targets in solid tumors (including brain, head and neck, melanoma, lung, breast and colon cancers). To this end, we develo...

Viruses may affect human health by altering host immunity and the genome, contributing to chronic disease and cancer. The purpose of this study was to examine evidence of oncogenicity accompanying integrations of non-hepatitis viruses into the liver cancer genome through analysis of a cohort of 147 Thai liver cancer patients comprised of 47 hepatoc...

The tumor microenvironment is a complex mixture of cell-types that interact with each other to affect tumor growth and clinical outcomes. To accelerate the discovery of such interactions, we develop CODEFACS (Confident Deconvolution For All Cell Subsets), a deconvolution tool that infers cell-type-specific gene expression in each sample from bulk e...

The U.S. Food and Drug Administration (FDA) recently approved the treatment with pembrolizumab, an immune checkpoint inhibitor (ICI) targeting PD1 (anti-PD1), for patients with advanced solid tumors with a high tumor mutational burden (TMB) (defined as TMB ≥10 mutations/Mb). However, following recent studies suggest that TMB levels and response to...

The FDA has recently approved high tumor mutational burden (TMB), defined by ≥10 mutations/Mb, as a biomarker for the treatment of solid tumors with pembrolizumab, an immune checkpoint inhibitor (ICI) that targets PD1. However, recent studies testify that high TMB levels are only able to stratify ICI responders in a subset of cancer types, where th...

In this work we develop a novel algorithm for reconstructing the genomes of ancestral individuals, given genotype or sequence data from contemporary individuals and an extended pedigree of family relationships. A pedigree with complete genomes for every individual enables the study of allele frequency dynamics and haplotype diversity across generat...

Background: The DNA sequences encoding ribosomal RNA genes (rRNAs) are commonly used as markers to identify species, including in metagenomics samples that may combine many organismal communities. The 16S small subunit ribosomal RNA (SSU rRNA) gene is typically used to identify bacterial and archaeal species. The nuclear 18S SSU rRNA gene, and 28S...

The goal of this study is to develop a new method to characterize taxonomically which microbes are present intracellularly in which cell types in the tumor microenvironment. The tumor microbiome impacts many aspects of tumor development including tumorigenesis, mutagenesis, response to chemotherapy and the immune response. A recent computational ap...

The tumor microenvironment (TME) is a complex mixture of cell-types that interact with each other to affect tumor growth and clinical outcomes. To accelerate the discovery of such interactions, we developed CODEFACS (COnfident DEconvolution For All Cell Subsets), a deconvolution tool inferring cell-type-specific gene expression in each sample from...

Modifier genes are believed to account for the clinical variability observed in many Mendelian disorders, but their identification remains challenging due to the limited availability of genomics data from large patient cohorts. Here, we present GENDULF (GENetic moDULators identiFication), one of the first methods to facilitate prediction of disease...

Background SARS-Cov-2 is a new virus causing a pandemic of primarily respiratory illness designated as Coronavirus Disease 2019 (COVID-19). This disease is associated with excess mortality, particularly among the elderly, raising concerns for public health. It is crucial to identify whether existing medications could protect against adverse outcome...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment syndrome, affecting a large proportion of the general population. Genetic susceptibility has been implicated in CTS, but the causative genes remain elusive. Here, we report the identification of two mutations in cartilage oligomeric matrix protein (COMP) that segregate with...

Motivation: Recent advances in single-cell sequencing (SCS) offer an unprecedented insight into tumor emergence and evolution. Principled approaches to tumor phylogeny reconstruction via SCS data are typically based on general computational methods for solving an integer linear program, or a constraint satisfaction program, which, although guarant...

Abstract The COVID‐19 pandemic caused by SARS‐CoV‐2 has is a global health challenge. Angiotensin‐converting enzyme 2 (ACE2) is the host receptor for SARS‐CoV‐2 entry. Recent studies have suggested that patients with hypertension and diabetes treated with ACE inhibitors (ACEIs) or angiotensin receptor blockers have a higher risk of COVID‐19 infecti...

Background: GenBank contains over 3 million viral sequences. The National Center for Biotechnology Information (NCBI) previously made available a tool for validating and annotating influenza virus sequences that is used to check submissions to GenBank. Before this project, there was no analogous tool in use for non-influenza viral sequence submiss...

Microbial taxa that are differentially abundant between cell types are likely to be intracellular. Here we describe a new computational pipeline called CSI-Microbes (computational identification of C ell type S pecific I ntracellular Microbes ) that aims to identify such putative intracellular species from single cell RNA-seq data in a given tumor...

Prognosis for young patients with breast cancer is generally poor, yet considerable differences in clinical outcome between individual patients exist. To understand the genetic basis of the disparate clinical courses, we collected tumors from 34 younger women, 17 with good and 17 with poor outcomes, as determined by disease-specific survival during...

Characterizing intratumor heterogeneity (ITH) is crucial to understanding cancer development, but it is hampered by limits of available data sources. Bulk DNA sequencing is the most common technology to assess ITH, but involves the analysis of a mixture of many genetically distinct cells in each sample, which must then be computationally deconvolve...

Computational reconstruction of clonal evolution in cancers has become a crucial tool for understanding how tumors initiate and progress and how this process varies across patients. The field still struggles, however, with special challenges of applying phylogenetic methods to cancers, such as the prevalence and importance of copy number alteration...