Programmable bacteria for the treatment of cancer
Inventors
Danino, Tal • Arpaia, Nicholas • Chowdhury, Sreyan • Gurbatri, Candice
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Assignees
National Institutes Of Health Nih US Department Of Health And Human Services Dhhs • Columbia University in the City of New York
Member
Columbia UniversityColumbia University is a leading Ivy League research university in New York City, founded in 1754. It comprises undergraduate and graduate programs across 17+ schools, a world-renowned medical center, and nearly 200 research centers and institutes. The Global Alliance for Preventing Pandemics (GAPP) in the Mailman School of Public Health is dedicated to capacity building through workforce development and democratization of technology to provide public health professionals in the Global South every opportunity to independently identify and contain pathogen outbreaks. GAPP focuses on sharing sustainable technologies and best technical practices involving sequencing, serological, and rapid diagnostics tools so public health teams are poised to achieve their very different goals addressing their varied and evolving needs. GAPP works closely with the US CDC, NIAID, WHO, GOARN, foundations dedicated to global health and medical equity, and local and regional ministries of health and education to address human health, and the ministries of livestock and fisheries to help address food security while fostering a culture of the open sharing of data.
Columbia University is a leading Ivy League research university in New York City, founded in 1754. It comprises undergraduate and graduate programs across 17+ schools, a world-renowned medical center, and nearly 200 research centers and institutes. The Global Alliance for Preventing Pandemics (GAPP) in the Mailman School of Public Health is dedicated to capacity building through workforce development and democratization of technology to provide public health professionals in the Global South every opportunity to independently identify and contain pathogen outbreaks. GAPP focuses on sharing sustainable technologies and best technical practices involving sequencing, serological, and rapid diagnostics tools so public health teams are poised to achieve their very different goals addressing their varied and evolving needs. GAPP works closely with the US CDC, NIAID, WHO, GOARN, foundations dedicated to global health and medical equity, and local and regional ministries of health and education to address human health, and the ministries of livestock and fisheries to help address food security while fostering a culture of the open sharing of data.
Publication Number
US-12350297-B2
Publication Date
2025-07-08
Expiration Date
Abstract
Disclosed herein are programmable bacteria for tumor-targeted immunotherapeutic delivery. In certain embodiments, the programmable bacteria comprise at least one synchronized lysis circuit contained in a single operon which are capable of being further engineered to cyclically produce anti-cancer therapeutic agents including but not limited to nanobodies against immune checkpoint inhibitors and over-expressed markers in cancers, toxins, tumor antigens, cytokines, and chemokines. In some embodiments, the programmable bacteria comprise at least one synchronized lysis circuit contained in a single operon and at least one plasmid producing a therapeutic agent, i.e., at least one plasmid comprising a nucleic acid sequence which encodes a therapeutic agent. The disclosure also provides methods of curing and treating cancer using the programmable bacteria.
Core Innovation
Disclosed herein are programmable bacteria for tumor-targeted immunotherapeutic delivery. In certain embodiments, the programmable bacteria comprise at least one synchronized lysis circuit contained in a single operon which are capable of being further engineered to cyclically produce anti-cancer therapeutic agents including but not limited to nanobodies against immune checkpoint inhibitors and over-expressed markers in cancers, toxins, tumor antigens, cytokines, and chemokines.
The synchronized lysis circuit can be integrated into the genome of the programmable bacteria or contained on a plasmid, and the programmable bacteria can further comprise at least one plasmid comprising a nucleic acid sequence which encodes a therapeutic agent, where in some embodiments the plasmid producing the therapeutic agent is a high copy plasmid. The disclosure provides compositions, solutions, cell cultures, pharmaceutical compositions, and kits comprising the programmable bacteria and methods of treating and curing cancer using the programmable bacteria.
The background identifies a need for improved delivery systems that provide controllable and local delivery of checkpoint blockade inhibitors to the tumor site to minimize adverse effects and to gain access to difficult hypoxic or non-vascularized tumors, and notes limitations of existing therapies including non-specificity, systemic toxicity, and limited patient subsets for targeted genomic alterations. The programmable bacteria are described as addressing these needs by providing controlled, local delivery of anti-cancer and other therapeutic agents with the potential to induce systemic adaptive immunity.
Claims Coverage
Independent claim identified: one independent claim (claim 1). The main inventive features extracted from claim 1 are listed below.
Synchronized lysis circuit integrated into the genome
At least one synchronized lysis circuit, contained in a single operon and integrated into the genome of the bacterium.
High copy plasmid encoding a therapeutic agent
At least one plasmid comprising a nucleic acid sequence which encodes a therapeutic agent, wherein the at least one plasmid is a high copy plasmid.
Tumor-targeted delivery with immune activation
Wherein the programmable bacterium delivers the therapeutic agent to a tumor and activates an immune response against the tumor.
SLC composition elements on a single operon
Wherein the at least one synchronized lysis circuit comprises a nucleic acid encoding a quorum-sensing gene, a nucleic acid encoding a lysis gene, a promoter, and a terminator contained on a single operon.
Claim 1 recites a programmable bacterium combining a synchronized lysis circuit contained in a single operon integrated into the genome, a high copy plasmid encoding a therapeutic agent, tumor-targeted delivery with activation of an immune response, and that the synchronized lysis circuit comprises a quorum-sensing gene, a lysis gene, a promoter, and a terminator on a single operon.
Stated Advantages
Localized release of therapeutic agents minimizes systemic toxicity by increasing local concentration of immunotherapy while preventing systemic exposure.
A synchronized lysing circuit contained in a single operon reduces possible horizontal gene transfer and serves as a biocontainment measure to confine the bacterial population to the tumor site.
Programmable bacteria with integrated lysis circuit demonstrated comparable therapeutic efficacy to clinically relevant monoclonal antibodies and in some instances greater therapeutic efficacy.
Combination therapies and cocktails produced by programmable bacteria can yield synergistic or enhanced therapeutic efficacy compared to individual therapies.
Local bacterial delivery can induce systemic adaptive immunity (abscopal effect) reducing growth of untreated tumors and decreasing metastasis.
Modularity and ease of engineering bacteria enable rapid production of multiple therapeutic agents and customizable ‘cocktail’ therapies.
Use of probiotic strains such as E. coli Nissle 1917 offers translational delivery routes and colonization of tissues such as liver metastases when delivered orally.
Documented Applications
Tumor-targeted immunotherapeutic delivery of anti-cancer therapeutic agents including nanobodies to checkpoint inhibitors and over-expressed markers in cancers, toxins, tumor antigens, cytokines, and chemokines.
Methods of treating and curing cancer, including primary and metastatic cancers, using programmable bacteria, compositions, or solutions comprising the programmable bacteria.
Inducing systemic adaptive immunity to limit or reduce the growth of untreated tumors (abscopal effect).
Administration routes explicitly described: intratumoral, intravenous, or oral administration of programmable bacteria or compositions comprising programmable bacteria.
Pharmaceutical compositions, solutions, cell cultures, and kits comprising the programmable bacteria for use in manufacture of a medicament or for treatment.
Use in combination with conventional cancer treatment or therapy and in combination regimens involving two or more programmable bacteria producing different or the same types of therapeutic agents.
Applications in human medical and veterinary medicine, including treatment of a wide range of cancers such as breast, melanoma, renal, prostate, pancreatic, colon, lung, esophageal, head and neck, liver, ovarian, cervical, thyroid, glioblastoma, and glioma as stated in the document.
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