Immune-enhancing rnas for combination with chimeric antigen receptor therapy
AssigneesThe Trustees of the University of Pennsylvania, Novartis AG
InventorsLexus R. Johnson, Carl H. June, Andy J. Minn
Life of this patent
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Abstract
The invention provides compositions and methods for treating diseases such as cancer. The invention also relates to a method of administering a chimeric antigen receptor (CAR) therapy and an additional therapeutic agent.
Claims33
1-3. (canceled)
A nucleic acid molecule comprising (1) a first nucleic acid molecule encoding a chimeric antigen receptor (CAR) molecule that binds to a first antigen, and (2) a second nucleic acid molecule comprising an RNA molecule or a nucleic acid molecule encoding an RNA molecule, wherein the RNA molecule comprises a first RNA sequence and a second RNA sequence, wherein the first RNA sequence is at least 80%, 85%, or 90% complementary to the second RNA sequence, wherein the first RNA sequence is at least 20 nucleotides in length and the second RNA sequence is at least 20 nucleotides in length, wherein the RNA molecule has one or more of the following properties:
- (i) the RNA molecule activates a pattern recognition receptor (PRR);
- (ii) the RNA molecule activates dendritic cells (DCs);
- (iii) the RNA molecule activates macrophages;
- (iv) the RNA molecule activates T cells;
- (v) the RNA molecule enhances immune infiltration into a tumor;
- (vi) the RNA molecule reduces tumor growth;
- (vii) the RNA molecule increases survival of the subject;
- (viii) the RNA molecule enhances the subject's responsiveness to the CAR-expressing cells or a checkpoint modulator;
- (ix) the RNA molecule does not bind or does not substantially bind to SRP9 and/or SRP14;
- (x) the RNA molecule is a functional variant of a naturally-existing RN7SL1 RNA molecule, wherein the RNA molecule retains all or part of the immunogenic property of the naturally-existing RN7SL1 RNA molecule, optionally wherein the RNA molecule shows reduced binding to SRP9 and/or SRP14 compared with the naturally-existing RN7SL1 RNA molecule;
- (xi) the RNA molecule is not polyinosinic:polycytidylic acid (poly I:C);
- (xii) the RNA molecule does not have RNAi or antisense inhibition activity or the RNA molecule has minimal RNAi or antisense inhibition activity;
- or
- (xiii) the RNA molecule has no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% sequence identity to a naturally-existing human gene.
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A kit comprising (1) a first nucleic acid molecule encoding a chimeric antigen receptor (CAR) molecule that binds to a first antigen, and (2) a second nucleic acid molecule comprising an RNA molecule or a nucleic acid molecule encoding an RNA molecule, wherein the RNA molecule comprises a first RNA sequence and a second RNA sequence, wherein the first RNA sequence is at least 80%, 85%, or 90% complementary to the second RNA sequence, wherein the first RNA sequence is at least 20 nucleotides in length and the second RNA sequence is at least 20 nucleotides in length, wherein the RNA molecule has one or more of the following properties:
- (i) the RNA molecule activates a pattern recognition receptor (PRR), e.g., retinoic acid-inducible gene I (RIG-I);
- (ii) the RNA molecule activates dendritic cells (DCs);
- (iii) the RNA molecule activates macrophages;
- (iv) the RNA molecule activates T cells;
- (v) the RNA molecule enhances immune infiltration into a tumor;
- (vi) the RNA molecule reduces tumor growth;
- (vii) the RNA molecule increases survival of the subject;
- (viii) the RNA molecule enhances the subject's responsiveness to the CAR-expressing cells or a checkpoint modulator;
- (ix) the RNA molecule does not bind or does not substantially bind to SRP9 and/or SRP14;
- (x) the RNA molecule is a functional variant of a naturally-existing RN7SL1 RNA molecule, wherein the RNA molecule retains all or part of the immunogenic property of the naturally-existing RN7SL1 RNA molecule, optionally wherein the RNA molecule shows reduced binding to SRP9 and/or SRP14 compared with the naturally-existing RN7SL1 RNA molecule;
- (xi) the RNA molecule is not polyinosinic:polycytidylic acid (poly I:C);
- (xii) the RNA molecule does not have RNAi or antisense inhibition activity or the RNA molecule has minimal RNAi or antisense inhibition activity;
- or
- (xiii) the RNA molecule has no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% sequence identity to a naturally-existing human gene.
A method of evaluating or predicting a subject's responsiveness to a CAR-expressing cell therapy, comprising acquiring a value for the level or activity of an unshielded RNA molecule, wherein the RNA molecule comprises the nucleotide sequence of SEQ ID NO:
- 1, wherein the value comprises a ratio of the amount of the RNA molecule to the amount of a protein that binds to the RNA molecule, wherein:
- (i) an increase in the value, as compared to a reference value, is indicative or predictive of increased responsiveness of the subject to the CAR-expressing cell therapy;
- and
- (ii) a decrease in the value, as compared to a reference value, is indicative or predictive of decreased responsiveness of the subject to the CAR-expressing cell therapy.
57-58. (canceled)
Dependencies are inferred from the claim text.