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Principal Investigator: Veenu Aishwarya
Organization: AUM LIFETECH, INC.
Fiscal Year: 2022
Award: $400,000
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Lung cancer accounts for >25% of cancer-related deaths in both men and women, making it the largest
source of cancer-related mortality. Despite advancements in surgical intervention, radiation, chemotherapy,
and immunotherapy, the 5-year survival rate for all types of lung cancer is 19%. The advent of immune
checkpoint inhibitor therapy is associated with remarkable efficacy is some patients with lung cancers, but
>75% of patients do not achieve meaningful clinical responses. Currently, T-regulatory (Treg) T cells are
regarded as one of the major obstacles to the successful clinical application of tumor immunotherapy. Tregs
contribute to the early establishment and progression of tumors, dampen effector cell responses by various
mechanisms, and promote and support pro-tumoral myeloid-derived suppressor cell development and
function. Tregs are thereby key to the immunosuppressive state of the tumor microenvironment that
prevents effective anti-tumor immune responses. Pre-clinical studies show targeting of Tregs, by their
depletion or functional modulation, can have significant therapeutic benefit, alone or in combination with
other immunomodulatory approaches. We and others have described the significant accumulation of
intratumoral Treg in lung cancer patients, and their increased intratumoral numbers correlate with poor
prognosis in many types of cancers.
Tregs are defined by their expression of the transcription factor FOXP3, which controls Treg development,
stability, and function. FOXP3 is the key element of multiple Treg-associated molecular complexes that
regulate the Treg-specific gene network and mechanisms of Treg-mediated immune regulation. FOXP3 is
located intracellularly, and previous efforts to target Tregs using their CD25 surface marker have
unintentionally co-targeted CD25+ activated T effector cells, causing a lack of robust anti-tumoral
efficiency in pre-clinical and clinical studies, along with severe adverse effects and toxicity. On the other
hand, Foxp3-specific depletion of Treg using tumor bearing DEREG transgenic mice, in combination with
anti-tumor vaccine therapy, resulted in robust antitumor immunity and an absence of overt autoimmunity.
Thus, there is an urgent and unmet need for therapies that can selectively target Treg cells, allowing the
body to mount its normal defenses against the cancer, without negative influences on the rest of the immune
system.
We have developed third generation FANA antisense oligonucleotides (FANA ASOs) that selectively
inhibit Tregs by knockdown of FOXP3 expression. This next generation of ASO differs from their
predecessors by chemical modifications that allow their efficient (gymnotic) self-delivery, even to resting
cells, and make them resistant to degradation by endogenous nucleases. In preliminary studies, anti-Foxp3
FANA ASOs reduced Foxp3 expression and suppressive functions of murine Tregs, and in 50% of
syngeneic mice bearing lung tumors, daily injection of FANA ASOs showed complete destruction of the
tumors as compared to scrambled controls and without overt toxicity. We now propose validation of newly
developed human FOXP3 FANAs, alone or in conjunction with anti-PD-1 monoclonal antibody therapy.
Aim 1 will assess their ability to knockdown FOXP3 and promote anti-tumor immunity in humanized mice
in vivo. Aim 2 will evaluate their activity against actual human lung cancer associated Treg cells.
Terms: <Adverse effects><Affect><Anti-Sense Oligonucleotides><Antineoplastic Vaccine><Antisense Agent><Antisense Oligonucleotides><Autoimmune Status><Autoimmunity><Award><Basal Transcription Factor><Basal transcription factor genes><CD25><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cancer Patient><Cancer Treatment><Cancer Vaccines><Cancers><Cause of Death><Cessation of life><Checkpoint inhibitor><Chemicals><Chemotherapy and Radiation><Chemotherapy and/or radiation><Clinical><Clinical Research><Clinical Study><Clinical Treatment Moab><Clinical Trials><Complex><Data><Death><Development><Development and Research><Effectiveness><Effector Cell><Elements><Evaluation><FOXP3><FOXP3 gene><Forkhead Box P3><Funding><Future><Gamma interferon><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Generations><Goals><Granzyme><Host resistance><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL2R><IL2RA><IL2RA gene><Immune Interferon><Immune checkpoint inhibitor><Immune infiltrates><Immune mediated therapy><Immune system><Immunocompetent><Immunodeficient Mouse><Immunologically Directed Therapy><Immunomodulation><Immunotherapy><Impairment><In Vitro><Infiltration><Injections><Interferon Gamma><Interferon Type II><Interferon-gamma><Interphase Cell><JM2><LYT3><Lead><Legal patent><Liver><Lung Neoplasms><Lung Tumor><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular><Monoclonal Antibodies><Monoclonal Antibody Therapy><Murine><Mus><Myeloid-derived suppressor cells><Neoplasm Vaccines><Non-dividing Cell><Nondividing Cell><Oligo><Oligonucleotides><Operative Procedures><Operative Surgical Procedures><PBMC><PD-1 antibody><PD1 antibody><PK/PD><Patents><Patients><Pb element><Peripheral Blood Mononuclear Cell><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase><Preparation><Process><Production><Prognosis><Pulmonary Cancer><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><R & D><R&D><RNA targeting drug><RNA targeting therapeutics><RNA-targeting therapy><Radiation><Regulatory T-Lymphocyte><Resistance><Rest><Resting Cell><SCURFIN><Services><Short interfering RNA><Small Interfering RNA><Source><Surface><Surgical><Surgical Interventions><Surgical Procedure><Survival Rate><T cell infiltration><T cell response><T cell tumor trafficking><T8 Cells><T8 Lymphocytes><TCGFR><Technology><Teff cell><Testing><Therapeutic><Toxic effect><Toxicities><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Transgenic Mice><Treg><Tumor Cell><Tumor Immunity><Tumor Vaccines><Tumor-infiltrating immune cells><VAC-TX><Vaccine Therapy><Validation><Woman><aPD-1><aPD1><allergic/immunologic body system><allergic/immunologic organ system><anti programmed cell death 1><anti-PD-1><anti-PD-1 Ab><anti-PD-1 antibodies><anti-PD-1 monoclonal antibodies><anti-PD1><anti-PD1 Ab><anti-PD1 antibodies><anti-PD1 monoclonal antibodies><anti-cancer immunotherapy><anti-cancer therapy><anti-programmed cell death protein 1><anti-programmed cell death protein 1 antibodies><anti-sense agent><anti-sense oligo><anti-tumor immune response><anti-tumor immune therapy><anti-tumor immunity><anti-tumor immunotherapy><anti-tumor vaccine><antiPD-1><antiPD1><anticancer immunotherapy><anticancer therapy><antisense oligo><antitumor immune response><antitumor immune therapy><antitumor immunity><antitumor immunotherapy><antitumor vaccine><base><cancer immunity><cancer immunotherapy><cancer microenvironment><cancer progression><cancer survival><cancer therapy><cancer type><cancer-directed therapy><check point immunotherapy><check point inhibition><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibition><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><chemotherapy><clinical applicability><clinical application><commercialization><cytotoxic CD8 T cells><cytotoxic CD8 T lymphocyte><developmental><effective therapy><effective treatment><effector T cell><efficacy study><gene network><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><humanized mice><humanized mouse><immune cell infiltrate><immune check point inhibition><immune check point inhibitor><immune check point therapy><immune checkpoint inhibition><immune checkpoint therapy><immune competent><immune infiltration><immune modulation><immune regulation><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive myeloid cells><immunotherapy for cancer><immunotherapy of cancer><in vivo><intratumoral immune cell><knock-down><knockdown><lFN-Gamma><lung cancer><mAb therapy><mAbs><mRNA><malignancy><men><men's><mortality><mouse model><murine model><myeloid suppressor cells><myeloid-derived suppressive cells><neoplasm immunotherapy><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new approaches><next generation><novel><novel approaches><novel strategies><novel strategy><nuclease><oligos><pharmacokinetics and pharmacodynamics><pre-clinical study><preclinical study><prevent><preventing><reconstitute><reconstitution><regulatory T-cells><research and development><resistant><response><siRNA><suppressive myeloid cells><surgery><therapeutic vaccination><transcription factor><tumor><tumor growth><tumor immune cell><tumor immune therapy><tumor immunotherapy><tumor microenvironment><tumor progression><vaccine for cancer><αPD-1><αPD1>