Biology subjects

Olson, M. L.

Publications and source records attributed to Olson, M. L..

6 recordsLinked to original sources

bioRxiv2026

VFUSE: Virulent Feature Understanding with Sparse autoEncoders

Generative models have shown remarkable progress in a variety of domains such as protein design, but such power enables the opaque generation of hazardous proteins. In this work, we introduce VFUSE (Virulent Feature Understanding with Sparse autoEncoders), a mechanistic interpretability approach that trains SAEs on diffusiontransformer activations to audit protein models for hazard-aware features. We apply VFUSE to RoseTTAFold3 and RFDiffusion3, popular openweight models for protein folding and synthesis. We find that for certain blocks, linear probes detect hazardous designs significantly better when fit in the SAE latent space over the original models representations: improving interpretability without sacrificing model performance. Furthermore, we identify monosemantic features from the SAE that fire only on hazardous designs at up to AUROC 0.84 (q < 10-13). To our knowledge this is the first SAE trained on an all-atom diffusion model and the first feature-level virulence audit of a protein design model, paving the way towards safe and interpretable protein design.

bioinformatics↗

bioRxiv2025

Drug tolerant persisters and immunotherapy persister cells exhibit cross-resistance and share common survival mechanisms

Persisters are a rare sub-population of tumor cells that survive anti-cancer therapy and are thought to be a major cause of recurrence. These cells have been identified following both drug- and immune-therapy but are generally considered to be distinct entities. Since both pharmacological agents and immune cells often kill via apoptosis, we tested a hypothesis that both types of cells survive based on reduced mitochondrial apoptotic sensitivity, which in turn would yield a similar and reciprocal multi-agent resistant phenotype. Supporting this hypothesis, we indeed observed that IPCs acquired a reduced sensitivity to multiple drug classes and radiotherapy, suggesting non-immune mechanisms are important in the survival of cancer cells after immunotherapy. Likewise, DTPs developed not only a reduced sensitivity to multiple drug classes and radiotherapy, but also acquired a reduced sensitivity to T cell killing. Both IPCs and DTPs developed a decreased sensitivity to mitochondrial apoptosis. A sub-population of IPCs downregulated antigen and upregulated PD-L1. Intriguingly, in the IPCs that didnt employ these mechanisms of resistance, a greater decrease in sensitivity to mitochondrial apoptosis was observed, suggesting that the presence or absence of a resistance mechanism can exert selective pressures over the emergence of others. Targeting anti-apoptotic dependencies in persisters increased sensitivity to chemotherapy or CAR T therapy. These results suggest that common biological mechanisms underly survival of persisters, whether derived from immune or drug therapy, and offer an explanation for the acquired cross-resistance to these two types of therapies often observed in the clinic. HighlightsO_LIImmunotherapy persister cells (IPCs) are less sensitive to drugs and radiation. C_LIO_LIDrug tolerant persisters (DTPs) are less sensitive to radiation and CAR T cell attack. C_LIO_LIIPCs and DTPs are less sensitive to mitochondrial apoptosis. C_LIO_LITargeting anti-apoptotic dependencies helps eliminate IPCs/DTPs. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/641492v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@fe98b4org.highwire.dtl.DTLVardef@db7bfdorg.highwire.dtl.DTLVardef@1a94469org.highwire.dtl.DTLVardef@1ca6b2c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Restricting CAR T Cell Trafficking Expands Targetable Antigen Space

Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS). We developed CAR T cells against one of these antigens, LINGO1, which is widely expressed in Ewing sarcoma (ES). To prevent CNS targeting, we engineered LINGO1 CAR T cells lacking integrin 4 (A4ko), an adhesion molecule essential for migration across the blood-brain barrier. A4ko LINGO1 CAR T cells were efficiently excluded from the CNS but retained efficacy against ES. We show that altering adhesion behavior expands the set of surface antigens targetable by CAR T cells. One sentence summaryAltering integrin-mediated adhesion provides tumor selectivity to CAR T cells by preventing homing to defined normal tissues but retaining tumor trafficking and anti-tumor activity. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/579002v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@256b53org.highwire.dtl.DTLVardef@a94775org.highwire.dtl.DTLVardef@1926f62org.highwire.dtl.DTLVardef@cec52e_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2022

Targeted delivery of interferon-gamma by synNotch T cells sensitizes neuroblastoma cells to T cell-mediated killing

Downregulation of HLA is one of the most common tumor escape mechanisms by enabling tumors to persist in the presence of tumor-reactive T cells. HLA loss is particularly common in children with high-risk neuroblastoma, who have a 50% long-term survival despite dose-intensive regimens. We have now developed an approach for the targeted induction of HLA to restore sensitivity of neuroblastoma cells to T cell-mediated killing. Using synNotch technology, we have generated T cells that, upon binding of the neuroblastoma surface antigen GD2, secrete IFN-{gamma} without conferring direct cytotoxic activity (snGD2i). Treatment with snGD2i cells induces high and durable expression of HLA on neuroblastoma cells in vitro and in vivo and restores sensitivity to TCR-transgenic T cells targeting neuroblastoma-specific antigens. In contrast, treatment does not lead to upregulation of immune checkpoints or systemically increased levels of IFN-{gamma}. Targeted delivery of IFN-{gamma} using snGD2i cells is a promising new strategy to address immune escape in neuroblastoma. STATEMENT OF SIGNIFICANCEHLA loss remains one of the most common and unsolved immune escape mechanisms in cancer cells. We have now developed a cell-based approach for the targeted upregulation of HLA on tumor cells, which efficiently sensitizes the malignant cells to killing by tumor-reactive T cells.

bioengineering↗

bioRxiv2021

Low-affinity CAR T cells exhibit reduced trogocytosis, preventing fratricide and antigen-negative tumor escape while preserving anti-tumor activity

Chimeric antigen receptor (CAR) T cells using the high-affinity CD19 binding domain FMC63 are an effective treatment for patients with relapsed and aggressive B cell lymphoma. However, antigen loss and poor CAR T cell persistence remain common causes for relapse in these patients. Using primary patient samples, we now show that FMC63-based CAR T cells confer rapid antigen loss in all major tumor types currently approved for treatment with CD19 CAR T cells via trogocytosis, the stripping of antigen from tumor cells by CAR T cells. We show that CAR T cell-mediated trogocytosis can be dramatically reduced across a wide range of B cell malignancies by replacing FMC63 with a low affinity CD19 antibody. This reduction in trogocytosis does not alter the direct anti-tumor activity of CD19 CAR T cells but prevents the emergence of antigen-negative tumor cells and significantly increases CAR T cell viability by reducing fratricide of CD19 CAR T cells following trogocytosis. TEASERA reduction in CAR affinity does not affect tumor killing but prolongs T cell persistence and prevents antigen-negative tumor escape.

bioengineering↗

bioRxiv2021

Fast off-rate CD229 chimeric antigen receptor T cells efficiently target multiple myeloma, spare T cells, and exhibit reduced trogocytosis

T cells expressing chimeric antigen receptors have shown remarkable therapeutic activity against different types of cancer. However, their wider use has been hampered by the potential for life-threatening toxicities due to the unintended targeting of healthy cells expressing low levels of the targeted antigen. We have now developed an affinity-tuning approach for the generation of minimally modified, low-affinity antibody variants derived from existing high-affinity antibodies. Using this approach, we engineered low affinity variants of the fully human CD229-specific antibody 2D3. Parental 2D3 originally efficiently targeted multiple myeloma cells but also healthy T cells expressing low levels of CD229. We demonstrate that CAR T cells based on a low affinity variant of 2D3, engineered to also express CJUN to increase CAR T cell expansion, maintain the parental antibodys anti-tumor activity but lack its targeting of healthy T cells in vitro and in vivo. In addition, we found that low affinity CD229 CAR T cells show reduced trogocytosis potentially augmenting CAR T cell persistence. The fast off-rate CAR produced using our affinity tuning approach eliminates a key liability of CD229 CAR T cells and paves the way for the effective and safe treatment of patients with multiple myeloma and other lymphoid malignancies. One sentence summaryRational T cell engineering yields low affinity CD229 CAR T cells overexpressing CJUN, which maintain the parental cells anti-tumor activity but eliminate killing of healthy T cells, increasing CAR T cell expansion, and decreasing trogocytosis.

bioengineering↗