University of Florida Archives - Page 2 of 3

2018

Young Investigator

Paul Castillo

Gainesville, FL

Enhancing T cell adoptive therapy against T cell acute lymphoblastic leukemia

“Despite standard of care with high dose chemotherapy and hematopoietic stem cell transplantation, children diagnosed with relapsed acute T cell lymphoblastic leukemias (T-ALL) have dismal prognoses. While adoptive cell therapy (ACT), particularly CAR T cell therapies, have shown to be effective against B cell malignancies, their success has not been translated to T cell malignancies due to inadequate ubiquitous targets and off-target effects with the potentially life-threatening depletion of large normal T cell populations.

We have taken a novel approach that uses adoptive cell therapy (ACT) to target unique tumor antigens derived from the T cell receptor (TCR) clonotypes of T-ALLs. TCRs are expressed on the T cell surface and interact, through a highly specific binding site (i.e. hypervariable region), with antigen bound major histocompatibility complexes (MHCs) to recognize and kill cells expressing foreign antigens (i.e. infected and tumor cells). TCR clonotypes are unique nucleotide sequences that results from the somatic recombination of the V, D, and J gene segments (TCR VDJ or hypervariable region) and defines each individual T cell clone. Given the clonal expansion of T cell malignancies, tumor derived TCR VDJ becomes an attractive immune target uniquely expressed on individual T-ALL cells, that differs from the TCR VDJ rearrangement of normal T cell populations.

Our goals for this project are to: 1) identify TCR VDJ-derived antigens to be leveraged as immune targets in murine models for T cell malignancies and 2) evaluate the immunogenicity, safety, and anti-tumor efficacy of TCR VDJ-specific T cells.

The significance of our study is to focus on the TCR clonotypes to be used as immune targets in a novel ACT platform. Targeting the TCR VDJ region will potentially overcome concerns regarding the depletion of normal T cell populations. Should these preclinical studies show anti-tumor efficacy targeting TCR VDJ clonotypes, this work will lead the advance into clinical application. Our institution has several ongoing clinical trials using a platform to generate tumor antigen specific T cells that constitute the base of this proposal.”

2014

Scholar Grant

Dr. Elias Sayour

Gainesville, FL

Current treatments for children with refractory brain tumors fail to control their disease necessitating the development of new treatments that will cure these tumors without hurting the patient. We propose harnessing the immune system to help fight and eradicate these tumors though the use of nanotechnology. Nanoparticles are small enough to deliver information to the immune system teaching it to fight cancer. We have pioneered suitable cancer vaccines from as few as 100 tumor cells, making possible the ability to offer cancer immunotherapy to the majority of patients from which small amounts of tumor tissue can be obtained during surgery or biopsy and our preliminary data has demonstrated that RNA extracted from these tumors can offer effective anti-tumor immunity in mice when loaded into nanoparticles.
We believe that RNA-nanoparticle vaccines targeting pediatric brain tumors will induce superior immune responses without toxicity leading to eradication of invasive tumors. To achieve this end, we will investigate where these particles travel, and the kind of immune responses they generate. We will then investigate how to improve these vaccines before establishing the most effective vaccine formulation. Then, we will examine their safety profile, and if they can generate tumor immunity in mouse models for pediatric cancer.
Brain tumors are the most frequent cause of cancer death in children and despite aggressive therapy, almost half the children diagnosed with the most common malignant brain tumors will die. Furthermore, survivors are often left with severe and lifelong treatment-associated deficits. RNA-nanoparticle vaccines can provide a more effective and specific therapy for these children without toxicity, and these particles have a wide range of clinical application for all malignancies. In summary, we propose engineering these particles to make them highly effective in teaching the immune system to eradicate the most common type of brain tumor in children.