Document text
Principal Investigator: Ernesto Guccione
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $350,358
Funding agency: National Cancer Institute
SUMMARY
Long-term protection from viral infections is mediated by both the humoral and cellular immune pathways.
Multiple Myeloma (MM) is the second most common hematological malignancy in the US and is characterized
by clonal plasma cell production, resulting in immune suppression and recurrent bacterial and viral infections.
SARS-CoV-2-specific antibody quantification are currently being used as clinical endpoints to determine
immune protection against COVID-19, and this information is even more relevant in immunocompromised
individuals who lack a humoral response, but are protected by the cellular immunity (i.e. MM patients).
Despite the urgent need to quantify cellular immunity, the complexity and lack of scalability of traditional
methods (e.g. ELISpot, flow cytometry) to detect antigen-specific T cells has so far prevented large scale studies.
To address this problem, we developed a direct qPCR-based rapid T cell activation (dqTACT) assay based
on ex vivo stimulation of whole blood samples with a pool of viral peptides (i.e.immunodominant peptides
covering SARS-CoV-2 Spike protein),
SARS-CoV-2 antigen-specific T cells, and CXCL10,
followed by direct amplification of IFNG 𝛾 or IL2 which are produced by
which is produced by monocytes and neutrophils in
,
response
to
T cell activation.
The overarching aim of this proposal is to develop and implement a qPCR method that can be used as a proxy
to measure the presence and functionality of antigen specific T cells in MM patients. Specifically, we hypothesize
that SARS-CoV-2 specific T cells might be a biomarker of previous infection and of efficacy of vaccination
strategies, complementary to quantification of the humoral response.
In the UH2 phase, we will define analytical sensitivity and specificity and establish cut-off/thresholds and
appropriate positive and quality controls, accuracy and false result rate by comparing the dqTACT assay with
the gold standard assays such as flow cytometry and ELISpot for measuring cellular immune responses.
In the UH3 phase, we will test the presence and persistence of cellular immunity to SARS-CoV-2 in
convalescent and vaccinated myeloma patients. Well annotated patient populations will be used to define
sensitivity, specificity, and thresholds with response to clinical end-points, such as presence and persistence of
humoral and cellular immunity to SARS-CoV-2. We will estimate the prevalence of the markers within vaccinated
myeloma patients. We will then extend our studies and use banked as well as fresh samples from our large
myeloma/immunocompromised population and healthy controls enrolled in IRB approved studies.
The overarching goal is to use the dqTACT assay to test the presence of T cells due to natural infection or
vaccination in myeloma patients, possibly aiding in nationwide booster strategies or passive antibody infusion
support to protect these vulnerable population.
Key deliverables an assay to rapidly quantify the functionality of T cellular immunity at scale.
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