Adoptive Cellular Therapy Using Oncolytic Virus Priming for Solid Tumors
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Solution Overview
Problem
Current adoptive cellular therapy strategies, particularly using chimeric antigen receptor (CAR) T cells, face challenges in targeting specific antigens on solid cancers due to the lack of unique cancer cell markers and the immunosuppressive tumor microenvironment, leading to poor efficacy.
Innovation Solution
Development of recombinant oncolytic viruses, such as HSV, engineered with tumor-specific antigens and tumor suppressor miR target sequences, to enhance targeting and replication in cancer cells while minimizing replication in non-target cells, combined with engineered antigen receptors to induce cytolysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are used to target cancer cells, then immune effector function is enhanced, but specificity and efficacy against solid cancers deteriorate due to lack of unique targetable antigens
Solution Approach 1:
The patent introduces a priming step where oncolytic viruses are administered first to infect and replicate in tumor cells, upregulating endogenous antigens and creating a more immunogenic tumor environment before CAR T cell infusion. This preliminary action enhances the ability of CAR T cells to recognize and target tumor cells by pre-conditioning the tumor microenvironment.
Solution Approach 2:
The oncolytic virus serves as an intermediary that bridges the gap between the immune system and solid tumors. The virus infects tumor cells, replicates, and triggers immune responses while also upregulating antigens that make tumors more visible to CAR T cells, thereby mediating enhanced targeting specificity.
2Reliability
If CAR T cells are engineered to recognize tumor antigens, then cytotoxic function is improved, but performance deteriorates due to immunosuppressive tumor microenvironment and physical barriers
Solution Approach 1:
The oncolytic virus performs preliminary anti-action by infecting and lysing tumor cells, thereby disrupting the immunosuppressive microenvironment and physical barriers before CAR T cells encounter the tumor. This pre-damage to the tumor structure reduces the suppressive effects and improves CAR T cell infiltration and function.
Solution Approach 2:
The patent converts the immunosuppressive tumor microenvironment from a harmful factor into a beneficial target. The oncolytic virus specifically infects and replicates in tumor cells within this microenvironment, using the tumor cells themselves as factories to produce viral progeny that further amplify the anti-tumor response and overcome suppression.
3Productivity
If oncolytic viruses replicate extensively in tumor cells, then therapeutic efficacy is improved, but safety deteriorates due to potential replication in non-target cells
Solution Approach 1:
The oncolytic virus is engineered with tumor-specific genetic elements that confer selective replication capability only in tumor cells. The virus possesses local quality differences - it can replicate in tumor cells but is restricted from replicating in normal cells, thereby achieving high therapeutic efficacy without off-target toxicity.
Solution Approach 2:
The patent employs parameter changes in the viral genome to achieve tumor-selective replication. By modifying viral genes to include tumor-specific promoters or regulatory elements, the virus's replication capability is tuned to be active only under tumor-specific conditions, maximizing efficacy while minimizing harm to non-target cells.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The engineered oncolytic viruses effectively target and replicate within cancer cells, overcoming immunosuppressive barriers and enhancing therapeutic efficacy against solid tumors.
Implementation Method 1
recombinant oncolytic viruses, such as HSV, engineered with tumor-specific antigens and tumor suppressor miR target sequences, to enhance targeting and replication in cancer cells
Implementation Method 2
one or more tumor suppressor micro-RNA (miR) target sequences
Data Source
AI summary
The invention provides improved compositions and methods for the treatment of solid cancers.