Cellular immunotherapy for repetitive administration
Inventors
Sourdive, David • Duclert, Aymeric • SIMON, Mathieu • Duchateau, Philippe • WILLIAMS, Alan Marc • Poirot, Laurent
Assignees
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Publication Number
US-12144825-B2
Publication Date
2024-11-19
Expiration Date
Abstract
The present invention provides composition kits and methods for treating cancer in a human by immunotherapy using successive doses of CAR-T cells with no or reduced anamnestic immune reaction in one individual (P).
Core Innovation
The invention relates to a method for immunotherapy for treating cancer in a human by genotyping and/or phenotyping the HLA molecules and/or HLA alleles of the patient. A dose of a first set of engineered allogeneic T cells is administered from a single donor, where the donor differs from the patient in specified HLA markers. The first set contains at least one chimeric antigen receptor (CAR) or one transgenic T-cell receptor (TCR) and inactivates at least one component of the endogenous TCR gene.
At least 30 days after the first administration, a dose of a second set of engineered allogeneic T cells is administered from a different single donor. The second set has no common HLA-A, HLA-B, HLA-C and HLA-DR alleles with those of the first set other than those fully matching the patient, and the second set also contains at least one CAR or one transgenic TCR and inactivates at least one component of the endogenous TCR gene. The approach uses controlled HLA matching and mismatching patterns across successive grafts.
The document further describes reducing immunogenicity of the engineered cells, including beta-2 microglobulin (B2M) deficiency and/or CIITA deficiency, endogenous TCR gene inactivation, and quantification and minimization of immunogenic antigens across successive grafts using HLA typing and related measurements. It also describes selection of pharmaceutical unit doses, timing between administrations, and additional treatment components such as lymphodepletion and an immunosuppressive regimen.
Claims Coverage
The claims cover sequential allogeneic engineered T-cell immunotherapy with patient HLA genotyping and/or phenotyping, a first donor-derived set with specified HLA differences and endogenous TCR gene inactivation, and a second donor-derived set from a different donor administered after at least 30 days with controlled HLA allele commonality. Both sets include at least one CAR or one transgenic TCR. The coverage includes three core inventive features plus dependent refinements.
Patient HLA genotyping and/or phenotyping
Genotyping and/or phenotyping the HLA molecules and/or HLA alleles of a patient before administering engineered allogeneic T cells.
First engineered allogeneic donor set with specified HLA differences and TCR inactivation
Administering a first set of engineered allogeneic T cells from a single donor having at least one difference from the patient in specified HLA markers, where the first set contains at least one CAR or one transgenic TCR and inactivates at least one component of the endogenous TCR gene.
Second engineered allogeneic donor set with controlled HLA allele commonality after at least 30 days
At least 30 days after the first set, administering a second set of engineered allogeneic T cells from a different single donor such that the second set has no common HLA-A, HLA-B, HLA-C and HLA-DR alleles with those of the first set other than those fully matching the patient, while also containing at least one CAR or one transgenic TCR and inactivating at least one component of the endogenous TCR gene.
Quantified HLA matching requirement for the first set
The first set of engineered allogeneic T cells matches the patient by at least eight of ten listed HLA markers.
Quantified dosing range for the first set
Administering the first set of engineered allogeneic T cells at a dose between 1.25×10^5 cells/kg and 5.05×10^6 cells/kg of the patient.
Immunosuppressive drug administration prior to first set
Treating a patient with an immunosuppressive drug for 2 to 5 days before administering the first set of engineered allogeneic T cells.
Use of fludarabine and/or cyclophosphamide as immunosuppressive drug
Performing the immunosuppressive drug treatment using fludarabine and/or cyclophosphamide.
Leukemia treatment using antigen selected as CD123, CD19, or CD22
Using an antigen selected as CD123, CD19, or CD22 to treat leukemia.
Overall, the claims cover sequential allogeneic engineered T-cell immunotherapy in which patient HLA is characterized, donor selection imposes defined HLA mismatch patterns across successive doses, and both doses include CAR/TCR modification with endogenous TCR gene inactivation. Dependent claims further add quantitative HLA-matching constraints, dosing ranges, pre-treatment immunosuppression, and exemplary leukemia-target antigens.
Stated Advantages
Reducing anamnestic immune responses and related toxicity while treating cancer.
Improving engraftment while reducing anti-CAR/HLA anamnestic responses.
Addressing resistance to treatment-related selective pressures.
Off-the-shelf allogeneic use.
Reduce anamnestic immune responses.
Reduce graft-versus-host disease.
Reduce host versus graft rejection.
Safety for successive allogeneic UCART administration.
Documented Applications
Immunotherapy for treating cancer in a human using sequential dosing of engineered allogeneic CAR-T or transgenic TCR T cells with controlled HLA relationships.
Treatment of leukemia using an antigen selected as CD123, CD19, or CD22.
CAR immunotherapy targeting many solid-tumor or leukemia antigens, including HtrA1 together with one or more selected cancer markers.
Successive allogeneic UCART administration across donor-mismatch scenarios, including cross-dosing CTL testing and assessment of anti-UCART antibodies and anamnestic responses in humans receiving successive UCART1/UCART2 doses.
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