About

Michael Birnbaum, PhD, is the Underwood-Prescott Professor and Associate Professor of Biological Engineering at MIT. His research focuses on decoding and manipulating immune recognition, particularly through protein engineering in cells to create novel immune treatments. His lab aims to understand and engineer diverse molecular repertoires of immune cells, such as T, B, and NK cells, to distinguish between normal cells and those altered by infection or cancer. The group employs techniques including protein biochemistry, protein engineering, sequencing, and bioinformatics to identify immune cells of interest, determine their antigen receptor sequences, and analyze immune responses to cancer and infection. This systematic approach helps to understand how immune system composition and dynamics influence immune response success or failure, with the goal of engineering more specific and potent immune responses. Birnbaum's background includes an A.B. in Chemical and Physical Biology from Harvard University and a Ph.D. in Immunology from Stanford University, where he studied T cell receptor recognition and activation, as well as immune receptors in neural development and neurodegenerative disease. He joined MIT's Department of Biological Engineering in 2016.

Research topics

• Biology
• Biochemistry
• Genetics
• Chemistry
• Immunology
• Cell biology
• Computational biology
• Medicine
• Cancer research
• Virology
• Physics

Selected publications

• A biomaterial platform for T cell-specific gene delivery

  UNC Libraries · 2026-04-21

  articleOpen accessSenior author
  PublisherDOI

• Scalable TCR synthesis and screening enable antigen reactivity mapping in vitiligo

  Immunity · 2026-01-28 · 1 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Activation-dependent lentiviruses enable antigen-specific T cell expansion and transduction

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-13

  article

  Abstract Cancer immunotherapies rely on tumor-specific T cells, which arise endogenously in most patients with cancer, but can be low frequency and poorly functional. Methods to specifically identify, expand, and manipulate tumor-specific T cells at the rare frequencies found in peripheral blood would enable new immunotherapeutic strategies. Here, we demonstrate an approach to virally transduce polyclonal tumor-reactive T cells across any MHC haplotype and in the absence of knowing the cognate antigen. By generating lentiviral vectors that selectively transduce cells expressing 4-1BB (CD137), a marker of T cell activation, we can transduce antigen-specific T cells with user-defined genetic cargoes that can selectively expand and track individual clonotypes via single-cell sequencing. Anti-4-1BB lentiviruses (4-1BB LVs) encoding therapeutic cargoes can also enhance antigen-specific T cells to extend survival in a xenograft model of human melanoma and transduce tumor-infiltrating T cells from patients with ovarian cancer. Overall, the 4-1BB LV platform targets antigen-specific T cells in a manner agnostic to both the antigen and presenting MHC, with potential applications in adoptive cell therapy manufacturing and TCR identification. One Sentence Summary Engineered lentiviral vectors targeting 4-1BB selectively activate, expand, and transduce antigen-specific T cells with immunomodulatory cargo.

  PublisherDOI

• Duration of Initial Viremia Modulates Functional Properties of HIV-specific T Cell Receptors

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-02

  articleOpen access

  Abstract Virus-specific CD8 + T cells are crucial in controlling chronic human viral infections such as HIV-1, but the effect of persistent antigen exposure on T cell repertoire formation is not well understood. In this study, we examined epitope-specific CD8 + T cell repertoires in people living with HIV-1, where duration of viremia following hyperacute infection was modulated by the time of initiation of continuous suppressive antiretroviral therapy (ART). After ART-induced undetectable viremia in persons expressing the same HLA class I allele, we analyzed the impact of early (n=6) versus delayed (n=6) ART initiation on the clonotypic composition, clonotypic cross-reactivity, functional avidity and memory differentiation profile of the HIV-specific T cell repertoire restricted by HLA-B*58:01. Using a panel of barcoded tetramers, we mapped T cell receptor (TCR) clonotypes specific for three dominant epitopes and their variants. Both groups exhibited polyclonal TCR repertoires with evidence of cross-reactivity, which was significantly enriched in donors with prolonged antigen exposure. Within this cohort, broadly cross-reactive clonotypes capable of recognizing all autologous variants were identified, but these were rare (<1%). Early ART initiation preserved repertoires characterized by higher-avidity TCRs and a relative enrichment of transitional memory CD8 + T cell subsets. These functional differences were not associated with differences in TRBV gene sharing, indicating that ART timing shapes repertoire quality and memory differentiation without altering TRBV gene bias. These findings demonstrate how antigen suppression dynamics differentially shape the breadth, functional sensitivity, and memory composition of the HIV-specific TCR repertoire, with implications for T cell-directed immunotherapies and HIV cure strategies. One Sentence Summary The duration of viral antigen exposure during early HIV infection shapes the functional quality, breadth, and memory composition of virus-specific CD8⁺ T cell receptor repertoires.

  PublisherDOI

• Interrogating antiviral antibody responses with multiplexed, high-throughput serum assays

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-06

  articleOpen accessSenior authorCorresponding

  The COVID-19 pandemic underscored the importance of rapidly analyzing antibody responses against emerging viruses. Existing techniques, however, are limited in their ability to probe antibodies' recognition of multiple native-conformation antigens simultaneously. To increase the throughput and multiplexability of antibody profiling, we developed Antibody Reactivity Characterization by Antibody-Dependent Enhancement (ARCADE). This assay employs an antigen-agnostic Fc receptor-expressing cell line and a library of antigen-displaying, genetically barcoded lentiviruses that, when mixed with serum, infect cells and integrate their barcodes at rates reflecting the relative abundances and affinities of the antigen-specific antibodies present. Verified using sera from COVID-19-convalescent and -vaccinated donors, ARCADE delivers insights that align with and expand upon those offered by established immunoassays, highlighting, for example, how an mRNA-based vaccine elicits broader and stronger antibody responses than an adenovirus vector-based vaccine. ARCADE can comprehensively assess how infection and vaccination impact antiviral antibody repertoires over time and across patient populations.

  PublisherOA PDFDOI

• In vivo CAR T cell engineering: design principles and open questions

  Trends in cancer · 2026-03-26

  articleSenior author
  PublisherDOI

• Dynamic estimation of metabolic state during CAR T cell production

  Cell Reports Methods · 2026-02-01

  articleOpen access

  We present a modeling framework that can perform real-time estimation of per-cell metabolic rates of T cells expanded ex vivo in a reactor. We validate our estimated rates using metabolic assays, show how average rates can be deconvoluted to rates of individual T cell phenotypes, and demonstrate applicability to different reactor types. Applying our tool to the expansion of both healthy and patient-derived cells in a perfusion-based microbioreactor, we offer proof-of-principle to show that correlations exist between early metabolic rates of T cells in culture and cellular attributes related to growth, differentiation, and exhaustion of the final product. Given the biological variation that exists in the growth and dynamics of patient-derived cells in culture, such modeling contributes to the overarching goal of improving the consistency of cell therapy through adaptive process control (APC).

  PublisherDOI

• Abstract LB-C006: Scalable TCR synthesis and screening enable antigen reactivity mapping

  Cancer Immunology Research · 2026-03-05

  articleSenior author

  Abstract Mapping T cells to their antigenic targets is critical to developing new targeted cancer therapies but remains highly challenging at scale. Single-cell datasets capture thousands of T cell receptors (TCRs) from tumor-infiltrating T cells but offer little data on antigen specificity. Here, we introduce an approach to synthesize and functionally screen tens of thousands of T cell receptors simultaneously. TCRAFT uses a modular strategy to reconstruct TCRs from sequences for under $1 per TCR while preserving TCRα-β pairing. We then integrate TCRAFT with RAPTR, a library-on-library approach to screen thousands of TCRs against antigens at scale. Using this workflow, we precisely reconstructed 3,808 TCRs from vitiligo blister fluid and screen them against hundreds of antigens to identify over 160 antigen-specific TCR clonotypes. By linking TCR specificity with corresponding single-cell gene expression data, we establish transcriptomic signatures of vitiligo-associated autoreactive T cells and correlate this signature with TILs in melanoma. Demonstrating scalability, we synthesize and screen over 30,800 TCRs at once from donors with pancreatic ductal adenocarcinoma to isolate antigen-specific TCRs. By enabling rapid and cost-effective TCR assembly and antigen mapping, our pipeline is accessible to any research group to identify clinically relevant TCRs and decode tumor-specific immune responses. Citation Format: Stephanie A. Gaglione, Rachit S. Mukkamala, Chirag Krishna, Blake E. Smith, Marc H. Wadsworth, Caleb R. Perez, Laura Schmidt-Hong, Erica L. Katz, Kyle J. Gellatly, Lester R. Ali, Jiao Shen, Scott Jelinsky, Patrick V. Holec, Qingyang H. Zhao, Amanda O. Chan, Ellen JK. Xu, Kellie M. Kravarik, Julia A. Guzova, Connor S. Dobson, Harshabad Singh, Manuel Garber, Michael Dougan, Stephanie K. Dougan, John E. Harris, Aaron Winkler, Michael E. Birnbaum. Scalable TCR synthesis and screening enable antigen reactivity mapping [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-C006.

  PublisherDOI

• Cell trajectory modulation: rapid microfluidic biophysical profiling of CAR T cell functional phenotypes

  Nature Communications · 2025-05-22 · 5 citations

  articleOpen access

  Chimeric Antigen Receptor (CAR) T cell therapy is a pivotal treatment for hematological malignancies. However, CAR T cell products exhibit batch-to-batch variability in cell number, quality, and in vivo efficacy due to donor-to-donor heterogeneity, and pre/post-manufacturing processes, and the manufacturing of such products necessitates careful testing, both post-manufacturing and pre-infusion. Here, we introduce the Cell Trajectory Modulation (CTM) assay, a microfluidic, label-free approach for the rapid evaluation of the functional attributes of CAR T cells based on biophysical features (i.e., size, deformability). CTM assay correlates with phenotypic metrics, including CD4:CD8 ratio, memory subtypes, and cytotoxic activity. Validated across multiple donors and culture platforms, the CTM assay requires fewer than 10,000 cells and delivers results within 10 minutes. Compared to labeled flow cytometry processing, the CTM assay offers real-time data to guide adaptive manufacturing workflows. Thus, the CTM assay offers an improvement over existing phenotypic assessments, marking a step forward in advancing CAR T cell therapy manufacturing. CAR T cell manufacturing faces significant challenges that impact cell quality and in vivo efficacy. This necessitates reliable cellular characterization methods. Here the authors present a real-time, label-free, microfluidic method that profiles cellular biophysical properties and correlates them to activation state and CAR T potency, facilitating the rapid phenotypic cell assessment during production.

  PublisherOA PDFDOI

• High-throughput screening for class I peptide MHC binding via yeast surface display

  Proceedings of the National Academy of Sciences · 2025-11-20 · 1 citations

  articleOpen accessSenior authorCorresponding

  T cells rely on short peptides presented by highly polymorphic major histocompatibility complexes (MHCs) to selectively initiate adaptive immune responses. Despite its importance, few techniques can systematically evaluate stable peptide presentation across diverse MHC alleles. Here, we describe a yeast display pipeline that can be deployed to rapidly screen peptides to identify class I pMHC binders across many alleles. Through this, we isolate unique biological phenomena such as alteration of the peptide presentation of HLA-B57 via interaction with the antiviral small molecule abacavir. We apply this approach to multiple pathogen proteomes ( Mycobacterium tuberculosis Type VII secretion substrates, SARS-CoV-2, Dengue, and Zika) to create a comprehensive list of potential T cell antigens. Altogether, this platform acts as a flexible tool to generate large unbiased datasets for class I peptide binding at a speed and scale competitive with the biological systems they represent.

  PublisherDOI

Recent grants

• Administrative Core

  NIH · $14.5M · 2014–2029

• Integrated Genomics and Bioinformatics

  NIH · $37.6M · 1997–2027

• Repertoire-scale T cell antigen identification via peptide-MHC lentivirus display

  NIH · $2.3M · 2020–2025

Frequent coauthors

• Nishant K. Singh

  Ragon Institute of MGH, MIT and Harvard

  53 shared

• Bruce D. Walker

  St Vincent's Hospital Sydney

  36 shared

• K. Christopher García

  Stanford University

  36 shared

• Brooke D. Huisman

  Harvard University

  32 shared

• Khloe S. Gordon

  Massachusetts Institute of Technology

  30 shared

• Taeyoon Kyung

  28 shared

• Patrick V. Holec

  Allen Institute

  28 shared

• Mary Carrington

  28 shared

Labs

• The Birnbaum LabPI

Education

• Ph.D., Biological Engineering

  Massachusetts Institute of Technology

  2000

• B.S., Bioengineering

  University of California, Berkeley

  1995