CMV Triplex Vaccine Support for Persistent Dual-Specific CAR T Cells
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Solution Overview
Problem
Existing T cell-based immunotherapies for cancer, such as CD19 CAR T cell therapy, face challenges with T cell persistence and activity over time, particularly in low target-antigen settings post-myeloablative HCT, leading to potential relapse and complications.
Innovation Solution
Combining CMV Triplex Vaccine with engineered T cells that recognize both CMV antigens and tumor-specific antigens, such as CD19, to enhance T cell proliferation and persistence through in vivo expansion, avoiding excessive exhaustion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If conventional CAR T cell therapy is used, then initial anti-tumor activity is achieved, but T cell persistence and activity deteriorate over time
Solution Approach 1:
The patent combines two distinct T cell recognition mechanisms into a single CAR T cell design: (1) the chimeric antigen receptor (CAR) for recognizing tumor antigens such as CD19, and (2) the endogenous T cell receptor (TCR) for recognizing CMV antigens. This dual-specificity design allows T cells to simultaneously engage both tumor targets and CMV antigens, providing sustained activation and persistence through the CMV component while maintaining anti-tumor activity through the CAR component.
Solution Approach 2:
The patent introduces CMV antigen presentation as an intermediary mechanism to sustain T cell activity. By engineering target cells to express CMV antigens (or utilizing endogenous CMV infection), the system creates a persistent source of T cell stimulation that indirectly supports long-term CAR T cell survival and function, bridging the gap between initial tumor recognition and sustained anti-tumor activity.
2Quantity of substance
If T cells are expanded ex vivo to increase dosage, then initial T cell numbers are improved, but T cell exhaustion increases
Solution Approach 1:
The patent performs preliminary selection and enrichment of CMV-specific T cells before CAR transduction. By pre-enriching for CMV-specific T cells through antigen stimulation and selection markers, the system ensures that the transferred cells already possess the desired dual-specificity phenotype, reducing the need for extensive post-transfer expansion and minimizing exhaustion risks associated with prolonged ex vivo culture.
3Quantity of substance
If myeloablative HCT is performed to achieve tumor cytoreduction, then tumor burden is reduced, but T cell engraftment reliability decreases
Solution Approach 1:
The patent exploits changes in the immunological parameter landscape following myeloablative HCT. The severe immunosuppression and antigen-presenting cell depletion created by myeloablation actually favor CAR T cell engraftment by reducing competition from endogenous T cells and increasing availability of niche resources. The CMV-specific TCR component further enhances engraftment by providing an alternative activation pathway that is less dependent on the depleted antigen-presenting cell infrastructure.
Data Source
AI summary
A method for treating a patient comprising: (a) providing a composition comprising a population of T cells expressing both a chimeric antigen receptor (CAR) and a T cell receptor specific for a cytomegalovirus (CMV) antigen; (b) administering the composition to the patient; and (c) administering to the patient a viral vector encoding: (i) CMV pp65 and (ii) a fusion protein comprising exon 4 of CMV protein IE1 (e4) and exon 5 of CMV protein IE2 (e5) either prior to or subsequent to administering the composition comprising a population of T cells to the patient is described.