Heini M Natri, PhD

Response to CAR T cell therapies in patients with brain tumors

Glioblastoma Multiforme (GBM) is an aggressive, lethal type of cancer that can occur in the brain or the spinal cord. The average survival time is 12-18 months after diagnosis, with only 5% of GBM patients surviving more than five years. GBM is resistant to traditional cancer therapies, calling for the urgent development of novel treatment approaches. Chimeric Antigen Receptor (CAR) T cell therapy shows promise in treating GBM and other brain tumors. We work on a number of correlative studies to better understand the patient response to CAR T therapy.

With our collaborators as City of Hope, we are investigating the factors impacting patient response to CAR T cell therapy in a number of pre-clinical and clinical trials across different CAR targets and cancer types, including adult and pediatric brain tumors. In trials spanning multiple CAR product types and CAR T therapy combined with other molecules, we are uncovering new mechanisms underlying treatment response and developing novel, more effective therapies to target these hard-to-treat tumors.

As a significant component of these studies, we characterize CAR T product and cells from patient cerebrospinal fluid, peripheral blood, and tumors by integrating multimodal data types (gene and surface protein expression, T cell receptor sequencing, spatial transcriptomics) on a single-cell level to gain a comprehensive understanding of the cellular and molecular drivers of response to CAR T therapy.

Read our paper on IL-13Rα2-targeting CAR T cells in the treatment of recurrent high-grade glioma, published in Nature Madicine.

Immune landscape in the tumor microenvironment

Cancer progression and response to therapies is determined by many factors, including intrinsic pathways, metabolic profiles, and the compositional and functional landscape of the tumor microenvironment. Different cell populations, including cytotoxic T cells, suppressive macrophages, and cancer associated fibroblasts (CAFs), all play an important role in shaping the TME. These processes are determined by both intrinsic pathways and extrinsic signaling.

Across a number of projects, organ systems, and tumor models, I use single-cell and spatial multiomics to unravel the immune dynamics in the TME of highly lethal tumors, such as brain tumors and peritoneal metastasis of gastric cancers.

Read our preprint "Overcoming myeloid-driven resistance to CAR T therapy by targeting SPP1".

Genetic underpinnings of gene expression and complex traits

Much of my work has focused on the genetic regulation of gene expression with the goal of connecting trait-associated variants to their regulatory targets and biological processes across tissues, cell types, and contexts.

Idiopathic Pulmonary Fibrosis (IPF) is a severe form of Interstitial Lung Disease (ILD) that typically leads to respiratory failure and death or a lung transplant within five years of diagnosis. In collaboration with Dr. Jonathan Kropski (Vanderbilt) and as a part of the Human Cell Atlas, The Banovich Lab has characterized heterogeneous cells types and gene regulatory networks in ILD and healthy lungs on a single-cell level.

In collaboration with Dr. Davis McCarthy and postdoctoral researcher Dr. Christina Azodi (Univ. Melbourne), integrating whole-genome genotype data and gene expression measurements from more than 450,000 single cells, we have explored genetic effects on gene regulation in disease-relevant cell types. By integrating these cell-type expression quantitative trait loci (eQTL) with IPF GWAS (genome-wide association study) statistics, we reveal the regulatory mechanisms connecting IPF GWAS loci to disease risk and progression.

Read our paper on cell type-specific and disease-associated eQTL, published in Nature Genetics.

Harnessing the power of genomics to understand co-occurring conditions in autism

Autistic individuals are disproportionately affected by a number of physical and psychiatric conditions, with a substantial impact on quality of life. This co-occurrence is shaped by both genetic architecture as well as environmental and lifestyle factors. My ongoing work leverages large-scale genomic, phenotypic, and functional data to disentangle the genetic, molecular, cellular, and lifestyle mechanisms underlying co-occurring conditions affecting the autistic population. This work is deeply informed by literature on stakeholder perspectives and priorities. I'm particularly invested in investigating opportunities for the better management of gastrointestinal symptoms and other somatic illnesses, and widely interested in the connections between neurodevelopmetal traits and physical and mental health.

I advocate for more socially responsible research, and for diversity, equity, and inclusion in genomics research and the workforce.

I believe that members of marginalized groups affected by genetics and genomics research must be adequately represented at all levels of research and decision-making. I believe that improving the recruitment, support, and retention of underrepresented minorities in the genetics and genomics workforce will benefit individuals, institutions, science, and society as a whole.

I'm particularly interested in the questions at the intersection of genetics, bioethics, and disability, and the societal and ethical implications of the implementation of genetic data and testing in research and clinical practice.

I have served in numerous workgroups to facilitate discussion and debate around genomics research on neurodevelopmental, psychiatric, and other sensitive traits. I serve in the Spectrum 10K advisory board redesigning the study following a community consultation. I'm a member of the HEARD (Healthy Engagement in Autism Research Dialogue) leadership committee. HEARD is an initiative coordinated by The NeuroDevelopmental Variability Initiative of the Broad Institute, together with the Autism Science Foundation, to promote dialogue between and among stakeholder groups, including researchers, clinicians, autistic individuals, and their family members.

I have led, facilitated, and participated in numerous collaborative efforts to advocate for more sustainable research practices in psychiatric and neurodevelomental research, particularly autism-related genomics studies. Supported by The Autism Intervention Research Network on Physical Health (AIR-P), I led and supervised an effort to develop a framework and guidelines for ethical genetic and genomic autism research. The Ethics in Genetics and Autism Research (EGAR) Workgroup is formed by autistic and non-autistic geneticists, bioethicists, genetic counselors, autism researchers, and advocates. Our paper Ethical challenges in autism genomics: Recommendations for researchers was published in the European Journal of Medical Genetics.

I have previously served in The Translational Genomics Research Institute's (TGen) Diversity, Equity, and Inclusion council.

View my CV with a complete list of publications and activities.