
Benjamin M LarimerUniversity of Alabama at Birmingham | UAB · Department of Radiology
Benjamin M Larimer
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42
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Publications (42)
Background
Immune-positron emission tomography (PET) imaging with tracers that target CD8 and granzyme B has shown promise in predicting the therapeutic response following immune checkpoint blockade (ICB) in immunologically “hot” tumors. However, immune dynamics in the low T-cell infiltrating “cold” tumor immune microenvironment during ICB remain p...
Cancer immunotherapy, including checkpoint blockade and cellular therapy, has become a cornerstone in cancer treatment. However, understanding the factors driving patient response or resistance to these therapies remains challenging. The dynamic interplay between the immune system and tumors requires new approaches for characterization. Biopsies an...
Introduction: Obesity is known to reduce efficacy for cancer treatment patients and is thought to modulate the tumor microenvironment and glucose metabolism. In this study, we aim to quantify obesity-induced differences in the breast cancer tumor microenvironment with positron emission tomography (PET) imaging of hypoxia, glucose metabolism, and gr...
The goal of this study is to develop a mathematical model that captures the interaction between evofosfamide, immunotherapy, and the hypoxic landscape of the tumor in the treatment of tumors. Recently, we showed that evofosfamide, a hypoxia-activated prodrug, can synergistically improve treatment outcomes when combined with immunotherapy, while evo...
One of the most aggressive forms of breast cancer involves the overexpression of human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in ∼25% of all breast cancers and is associated with increased proliferation, increased rates of metastasis, and poor prognosis. Treatment for HER2-positive breast cancer has vastly improved since t...
Background
Patients with chronic lymphocytic leukemia (CLL) have reduced seroconversion rates and lower binding antibody (Ab) and neutralizing antibody (NAb) titers than healthy individuals following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccination. Here, we dissected vaccine-mediated humoral and cellular responses to u...
Background: Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer related death with a 5-year survival rate at 11%. New systemic therapies for patients with PDAC are desperately needed. Upregulation or exposure of a new protein on the tumor cell surface can serve as a therapeutic or diagnostic target. Here, we highlight our rec...
Chronic lymphocytic leukemia (CLL) patients have lower seroconversion rates and antibody titers following SARS-CoV-2 vaccination, but the reasons for this diminished response are poorly understood. Here, we studied humoral and cellular responses in 95 CLL patients and 30 healthy controls after two BNT162b2 or mRNA-2173 mRNA immunizations. We found...
The adaptive immune response plays a critical role in detecting, eliminating, and creating a memory towards foreign pathogens and malignant cells. Demonstration of the specific and effective target killing of T cells in cancer has reignited interest in the study and therapeutic manipulation of the interaction between tumor and immune system. To bot...
Purpose/Objective(s)
Radiation can alter the tumor microenvironment and produce a corresponding immune response in tumors that have not been irradiated by generating a local inflammatory response and enhancing recognition of distant tumor cells, which is termed the “abscopal effect”. We previously designed a positron emission tomography (PET) trace...
Objective: Immune checkpoint blockades have shown a great promise in cancer therapy. However, as the overall response rate varies, there is a profound unmet need to monitor the treatment efficacy and predict therapeutic responders.
Methods: In vivo blocking and biodistribution studies were performed to validate the specificity of [89Zr]-mouse-CD4 a...
Advancements in monitoring and predicting of patient-specific response of triple negative breast cancer (TNBC) to immunotherapy (IMT) with and without chemotherapy are needed. Using granzyme B-specific positron emission tomography (GZP-PET) imaging, we aimed to monitor changes in effector cell activation in response to IMT with chemotherapy in TNBC...
Quantification of the anti-SARS-CoV-2 antibody response has proven to be a prominent diagnostic tool during the COVID-19 pandemic. Antibody measurements have aided in the determination of humoral protection following infection or vaccination and will likely be essential for predicting the prevalence of population level immunity over the next severa...
Preclinical nuclear molecular imaging speeds up the mean time from synthesis to market, in drug development process. Commercial imaging systems have in general high cost, require high-cost service contracts, special facilities and trained staff. In the current work, we present β-eye, a benchtop system for in vivo molecular screening of labeled comp...
The efficacy of adoptive cell therapy for solid tumours is hampered by the poor accumulation of the transferred T cells in tumour tissue. Here, we show that forced expression of C-X-C chemokine receptor type 6 (whose ligand is highly expressed by human and murine pancreatic cancer cells and tumour-infiltrating immune cells) in antigen-specific T ce...
Purpose:
Hypoxia is a common characteristic of many tumor microenvironments, and it has been shown to promote suppression of anti-tumor immunity. Despite strong biological rationale, longitudinal correlation of hypoxia and response to immunotherapy has not been investigated.
Experimental design:
In this study, we probed the tumor and its surroun...
Purpose:
Standard therapy for HER2+ breast cancers includes HER2 inhibition. While HER2 inhibitors have significantly improved therapeutic outcomes, many patients remain resistant to therapy. An important intrinsic resistance mechanism to HER2 inhibition in some breast cancers is dynamic upregulation of HER3. Increase in HER3 expression that occur...
ABSTRACT IMPACT: Insights from this project will provide clinical guidance in treatment of immunotherapy in triple negative breast cancer and identify early imaging biomarkers of treatment response. OBJECTIVES/GOALS: Significant research that addresses monitoring and predicting patient response of triple negative breast cancer (TNBC) to immunothera...
Paclitaxel (PTX) treatment efficacy varies in breast cancer, yet the underlying mechanism for variable response remains unclear. This study evaluates whether human epidermal growth factor receptor 2 (HER2) expression level utilizing advanced molecular positron emission tomography (PET) imaging is correlated with PTX treatment efficacy in preclinica...
Background: Although a portion of triple negative breast cancer (TNBC) is sensitive to chemotherapeutic treatment with agents such as paclitaxel (PTX), patients have a high risk of recurrence and short overall and progression-free survival. Clinical trials for TNBC using immune checkpoint inhibitors such as anti-programmed cell death 1 (PD1) have m...
Background: Standard therapy for HER2+ breast cancers includes HER2 inhibition. While HER2 inhibitors have modestly improved outcomes, they have not had nearly the original anticipated therapeutic efficacy, with only a modest improvement in survival in both the metastatic and adjuvant setting. An important intrinsic resistance mechanism to HER2 inh...
The use of biomarkers is integral to the routine management of cancer patients, including diagnosis of disease, clinical staging and response to therapeutic intervention. Advanced imaging metrics with CT, MRI, and PET are used to assess response during new drug development and in cancer research for predictive metrics of response. Key components an...
Background
Cancer immunotherapy research is expanding to include a more robust understanding of the mechanisms of treatment response and resistance. Identification of drivers of pro-tumor and anti-tumor immunity during treatment offers new strategies for effective alternative or combination immunotherapies. Currently, tissue or blood samples are co...
A hallmark of prostate cancer progression is dysregulation of lipid metabolism via overexpression of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis. Metastatic castration-resistant prostate cancer (mCRPC) develops resistance to inhibitors of androgen receptor (AR) signaling through a variety of mechanisms, including the em...
Purpose:
The lack of a timely and reliable measure of response to cancer immunotherapy has confounded understanding of mechanisms of resistance and subsequent therapeutic advancement. We hypothesized that PET imaging of granzyme B using a targeted peptide, GZP, could be utilized for early response assessment across many checkpoint inhibitor combin...
Tremendous efforts are currently dedicated to the development of novel therapies targeting the androgen receptor (AR), the major driver of prostate cancer disease and its progression to castration resistance. The ability to non-invasively interrogate AR expression over time in murine models of prostate cancer would permit longitudinal preclinical a...
Purpose:
HER3 (ERBB3) is a receptor tyrosine kinase that is implicated in treatment resistance across multiple cancers, including those of the breast, lung, and prostate. Overexpression of HER3 following targeted therapy can occur rapidly and heterogeneously both within a single lesion and across sites of metastasis, making protein quantification...
While cancer immunotherapy can produce dramatic responses, only a minority of patients respond to treatment. Reliable response biomarkers are needed to identify responders, and conventional imaging modalities have not proved adequate. Here, we provide a preclinical proof of concept for the use of granzyme B, a downstream effector of tumoral cytotox...
Methods:
A CD3 PET imaging agent targeting T cells was synthesized to test the role of such imaging as a predictive marker. The (89)Zr-p-isothiocyanatobenzyl-deferoxamine-CD3 PET probe was assessed in a murine tumor xenograft model of anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) immunotherapy of colon cancer.
Results:
Imaging on day 14 reveale...
Methods:
Anti-EGFR-F(ab')2and anti-HER3-F(ab')2were generated from monoclonal antibodies by enzymatic digestion, conjugated to DOTA, and labeled with(64)Cu. A panel of breast cancer cell lines was treated with increasing concentrations of the AKT inhibitor GDC-0068 or the PI3K inhibitor GDC-0941. Pre and post treatment expression of EGFR and HER3...
Due to the heterogeneity of ERBB2-expression between tumors and over the course of treatment, a non-invasive molecular imaging agent is needed to accurately detect overall ERBB2 status. Peptides are a highly advantageous platform for molecular imaging, since they have excellent tumor penetration and rapid pharmacokinetics. One limitation of peptide...
Personalized medicine is at the forefront of cancer diagnosis and therapy. Molecularly targeted therapies such as trastuzumab and tamoxifen have enhanced prognosis of patients with cancers expressing ERBB2 and the estrogen receptor, respectively. One obstacle to targeted therapy is the development of resistance. A targeted peptide that could distin...
The goal of this study was to improve the pharmacokinetic properties and specificity of an ERBB2-targeted peptide for SPECT imaging.
Bacteriophages (phages) displaying the ERBB2 targeting sequence, KCCYSL, flanked by additional random amino acids were used for in vivo selections in mice-bearing ERBB2-expressing MDA-MB-435 human breast xenografts. P...
ErbB-2 is a type 1 receptor tyrosine kinase over-expressed on ~30% of breast cancers and is an attractive target for the development of new diagnostic and therapeutic agents. In this study, an ErbB-2-targeting peptide, KCCYSL, previously isolated using bacteriophage display, was radiolabeled with [99mTc(H2O)3(CO)3]+ and examined for breast cancer i...