US 2023/0398149 A1 · CAR T CELL THERAPY IN PATIENTS WHO HAVE HAD PRIOR ANTI-CANCER ALKYLATOR THERAPY

Abstract

Provided herein are uses of chimeric antigen receptors (CARs) for treating a tumor or a cancer (such as B cell related cancer, e.g., multiple myeloma). In addition, an optimal washout period for commencing a therapy for the treatment of a condition in a subject after a prior exposure can be determined by receiving, for each of a plurality of subjects, prior treatment history data. Left-censored data can then be derived from the prior treatment history data for each of the subjects that includes a washout period and event or censor. A time scale of the left-censored treatment data is then inverted to result in right-censored treatment data. The right-censored treatment data is then applied to a time-to-event (TTE) model that associates one or more variables of interest with a time since exposure to the prior exposure. A maximally selected log-rank statistic across a plurality of cutoffs within a pre-defined percentile range is computed for continuous variables within the one or more variables of interest. One or more variables and associated cutoffs for the continuous variables having a maximally selected log-rank statistic below a first pre-defined threshold are then identified. A test statistic of each (n−1) strata relative to a reference stratum is then computed for ordinal or categorical variables within the one or more variables of interest. One or more ordinary or categorical variables and associated strata having a test statistic below a second pre-defined threshold, relative to the reference stratum are identified. An optimal washout period is then determined for the therapy based on the cutoff having a lowest value below the pre-defined threshold and relative to a median of subject values below the pre-defined threshold and a median of subject values above the pre-defined threshold.

Claims126

Dependent claims

A method of treating a tumor or a cancer in a subject in need thereof, comprising:

(a) administering to the subject an alkylating agent;
(b) isolating peripheral blood mononuclear cells (PBMCs) from the subject at least about six (6) months after step (a);
(c) determining that at least about 20% of the PBMCs are T cells;
(d) on the basis of the determination in step (c), subsequently manufacturing chimeric antigen receptor (CAR) T cells from the PBMCs;
and
(e) administering the CAR T cells to the subject.

3 more elements

A method of treating a tumor or a cancer in a subject in need thereof, comprising:

(a) isolating peripheral blood mononuclear cells (PBMCs) from the subject, and determining that at least about 20% of the PBMCs are T cells;
(b) on the basis of the determination in step (a), subsequently manufacturing chimeric antigen receptor (CAR) T cells from the PBMCs;
and
(c) administering to the subject the CAR T cells, wherein, prior to step (a), the subject had previously received an alkylating agent for treatment of the cancer.

1 more element

A method of treating a tumor or a cancer in a subject in need thereof, comprising:

(a) isolating peripheral blood mononuclear cells (PBMCs) from the subject;
(b) manufacturing chimeric antigen receptor (CAR) T cells from the PBMCs;
and
(c) administering to the subject the CAR T cells, wherein the subject had previously received an alkylating agent for treatment of the cancer;
wherein step (a) occurs at least about six months after the subject received the alkylating agent.

2 more elements

A method of treating a tumor or a cancer in a subject in need thereof, wherein the subject has been administered an alkylating agent, comprising:

(a) determining that the subject has not been administered the alkylating agent less than about six (6) months prior to the determining step;
(b) isolating peripheral blood mononuclear cells (PBMCs) from the subject;
(c) manufacturing chimeric antigen receptor (CAR) T cells from the PBMCs;
and
(d) administering to the subject the CAR T cells.

2 more elements

A method of treating a tumor or a cancer in a subject in need thereof, wherein the subject has been administered an alkylating agent, comprising:

(a) isolating peripheral blood mononuclear cells (PBMCs) from the subject;
(b) manufacturing chimeric antigen receptor (CAR) T cells from the PBMCs;
and
(c) administering to the subject the CAR T cells, wherein, at the time of the isolating, the subject has been determined to have been administered the alkylating agent at least about six (6) months prior.

1 more element

A method of treating a tumor or a cancer in a subject in need thereof, wherein the subject has been administered an alkylating agent, comprising administering to the subject T cells expressing a chimeric antigen receptor (CAR T cells) manufactured from peripheral blood mononuclear cells PBMCs isolated from the patient, wherein, at the time said PBMCs are isolated, the subject has last received the alkylating agent at least about six (6) months prior to the time the PBMCs are isolated.

A method of manufacturing chimeric antigen receptor (CAR) T cells from a subject, comprising:

(a) administering to the subject an alkylating agent for treatment of a tumor or a cancer;
(b) isolating peripheral blood mononuclear cells (PBMCs) from the subject at least about six months after step (a);
and
(c) manufacturing chimeric antigen receptor (CAR) T cells from the PBMCs.

1 more element

A method of manufacturing chimeric antigen receptor (CAR) T cells from a subject, comprising:

(a) isolating peripheral blood mononuclear cells (PBMCs) from the subject, and determining that at least about 20% of the PBMCs are T cells;
and
(b) on the basis of the determination in step (b), subsequently manufacturing chimeric antigen receptor (CAR) T cells from the PBMCs;
wherein, prior to step (a), the subject had previously received an alkylating agent for treatment of a tumor or a cancer.

1 more element

A method of manufacturing chimeric antigen receptor (CAR) T cells from a subject, comprising:

(a) isolating peripheral blood mononuclear cells (PBMCs) from the subject;
and
(b) manufacturing chimeric antigen receptor (CAR) T cells from the PBMCs;
wherein the subject had previously received an alkylating agent for treatment of a tumor or a cancer;
wherein step (a) occurs at least about six months after the subject received the alkylating agent.

2 more elements

A method of manufacturing chimeric antigen receptor (CAR) T cells from a subject, wherein the subject has been administered an alkylating agent for treatment of a tumor or a cancer, comprising:

a. determining that the subject has not been administered the alkylating agent less than about six (6) months prior to the determining step;
b. isolating peripheral blood mononuclear cells (PBMCs) from the subject;
and
c. manufacturing chimeric antigen receptor (CAR) T cells from the PBMCs.

1 more element

A method of manufacturing chimeric antigen receptor (CAR) T cells from a subject, wherein the subject has been administered an alkylating agent for treatment of a tumor or a cancer, comprising:

(a) isolating peripheral blood mononuclear cells (PBMCs) from the subject;
and
(b) manufacturing chimeric antigen receptor (CAR) T cells from the PBMCs;
wherein, at the time of the isolating, the subject has been determined to have been administered the alkylating agent at least about six (6) months prior.

1 more element

A method for determining an optimal washout period for commencing a therapy for treatment of a condition in a subject after a prior exposure, the method comprising:

receiving, for each of a plurality of subjects, prior treatment history data;
deriving, from the prior treatment history data, left-censored treatment data for each of the subjects comprising a washout period and event or censor;
inverting a time scale of the left-censored treatment data to result in right-censored treatment data;
applying the right-censored treatment data to a time-to-event (TTE) model that associates one or more variables of interest with a time since exposure to the prior exposure;
computing, for continuous variables within the one or more variables of interest, a maximally selected log-rank statistic across a plurality of cutoffs within a pre-defined percentile range;
identifying, for the continuous variables within the one or more variables of interest, the one or more variables and associated cutoff having a maximally selected log-rank statistic below a first pre-defined threshold;
computing, for ordinal or categorical variables within the one or more variables of interest, a test statistic of each (n−1) strata relative to a reference stratum;
identifying, for the ordinal or categorical variables within the one or more variables of interest, the one or more variables and associated strata having a test statistic below a second pre-defined threshold, relative to the reference stratum;
and
determining an optimal washout period for the therapy based on the cutoff having a lowest value below the pre-defined threshold and relative to a median of subject values below the pre-defined threshold and a median of subject values above the pre-defined threshold.

7 more elements

Dependencies are inferred from the claim text.

Car t cell therapy in patients who have had prior anti-cancer alkylator therapy

Life of this patent

Car t cell therapy in patients who have had prior anti-cancer alkylator therapy

Life of this patent

Abstract

Claims126