TREATMENT METHODS
Methods and compositions for identifying tumor antigens of human lymphocytes, and for identifying subjects for cancer therapy, are provided herein.
1 - 282 . (canceled)
283 . An immunogenic composition comprising one or more antigens or immunogenic fragments thereof;
wherein the one or more antigens are selected by a method comprising:
a) obtaining, providing, or generating a library comprising bacterial cells or beads comprising a plurality of tumor antigens, wherein each bacterial cell or bead of the library comprises a different tumor antigen;
b) contacting the bacterial cells or beads with antigen presenting cells (APCs) from a subject, wherein the APCs internalize the bacterial cells or beads;
c) contacting the APCs with lymphocytes from the subject, under conditions suitable for activation of lymphocytes by a tumor antigen presented by one or more APCs;
d) determining whether one or more lymphocytes are activated by one or more tumor antigens presented by one or more APCs by assessing a level of expression and/or secretion of one or more immune mediators;
e) identifying each activating tumor antigen as (i) an antigen that stimulates the level of expression and/or secretion of one or more immune mediators, or (ii) an antigen that inhibits and/or suppresses the level of expression and/or secretion of one or more immune mediators; and
f) selecting from among the identified tumor antigens (i) one or more antigens that increase a level of expression and/or secretion of one or more immune mediators associated with at least one beneficial response to cancer, (ii) one or more tumor antigens that inhibit and/or suppress a level of expression and/or secretion of one or more immune mediators associated with at least one deleterious and/or non-beneficial response to cancer, (iii) one or more antigens that increase a level of expression and/or secretion of one or more immune mediators associated with at least one deleterious and/or non-beneficial response to cancer, and/or (iv) one or more tumor antigens that inhibit and/or suppress a level of expression and/or secretion of one or more immune mediators associated with at least one beneficial response to cancer.
284 . The immunogenic composition of claim 283 , wherein the immunogenic composition does not comprise: (iii) one or more tumor antigens that increase level of expression and/or secretion of one or more immune mediators associated with at least one deleterious and/or non-beneficial response to cancer, and/or (iv) one or more tumor antigens that inhibit and/or suppress level of expression and/or secretion of one or more immune mediators associated with at least one beneficial response to cancer, or immunogenic fragments thereof.
285 . The immunogenic composition of claim 283 , wherein the immunogenic composition comprises: (i) one or more antigens that increase a level of expression and/or secretion of one or more immune mediators associated with at least one beneficial response to cancer, and/or (ii) one or more tumor antigens that inhibit and/or suppress a level of expression and/or secretion of one or more immune mediators associated with at least one deleterious and/or non-beneficial response to cancer, or immunogenic fragments thereof.
286 . A method of manufacturing an immunogenic composition, the method comprising:
combining one or more selected antigens or immunogenic fragments thereof and a carrier;
wherein the one or more selected antigens are selected by a method comprising:
a) obtaining, providing, or generating a library comprising bacterial cells or beads comprising a plurality of tumor antigens, wherein each bacterial cell or bead of the library comprises a different tumor antigen;
b) contacting the bacterial cells or beads with antigen presenting cells (APCs) from a subject, wherein the APCs internalize the bacterial cells or beads;
c) contacting the APCs with lymphocytes from the subject, under conditions suitable for activation of lymphocytes by a tumor antigen presented by one or more APCs;
d) determining whether one or more lymphocytes are activated by one or more tumor antigens presented by one or more APCs by assessing a level of expression and/or secretion of one or more immune mediators;
e) identifying each activating tumor antigen as (i) an antigen that stimulates the level of expression and/or secretion of one or more immune mediators, or (ii) an antigen that inhibits and/or suppresses the level of expression and/or secretion of one or more immune mediators; and
f) selecting from among the identified tumor antigens (i) one or more antigens that increase a level of expression and/or secretion of one or more immune mediators associated with at least one beneficial response to cancer, (ii) one or more tumor antigens that inhibit and/or suppress a level of expression and/or secretion of one or more immune mediators associated with at least one deleterious and/or non-beneficial response to cancer, (iii) one or more antigens that increase a level of expression and/or secretion of one or more immune mediators associated with at least one deleterious and/or non-beneficial response to cancer, and/or (iv) one or more tumor antigens that inhibit and/or suppress a level of expression and/or secretion of one or more immune mediators associated with at least one beneficial response to cancer.
287 . The method of claim 286 , wherein the APCs are human APCs isolated from the subject.
288 . The method of claim 286 , wherein the APCs and lymphocytes are isolated from peripheral blood.
289 . The method of claim 286 , wherein the lymphocytes are derived from a cancer or tumor.
290 . The method of claim 286 , wherein lymphocyte activation is determined by (i) assessing a level of one or more expressed or secreted immune mediators that is at least about 20% higher or lower than a control level; (ii) assessing a level of one or more expressed or secreted immune mediators that is at least two standard deviations greater or lower than the mean of a control level; and/or (iii) assessing a level of one or more expressed or secreted immune mediators that is at least 2 median absolute deviations (MADs) greater or lower than a median response level to a control.
291 . The method of claim 286 , wherein lymphocyte non-responsiveness is determined by (i) assessing a level of one or more expressed or secreted immune mediators that is within about 20% of a control level; (ii) assessing a level of one or more expressed or secreted immune mediators that is less than one standard deviation higher or lower than the mean of a control level; and/or (iii) assessing a level of one or more expressed or secreted immune mediators that is less than one median absolute deviation (MAD) higher or lower than a median response level to a control.
292 . The method of claim 286 , wherein the APCs are provided in an array, and wherein the APCs in each location of the array are contacted with a set of bacterial cells, each set comprising a different tumor antigen.
293 . A method of identifying a subject as a candidate for cancer therapy, the method comprising:
1) obtaining a subject response profile, wherein the subject response profile is generated by:
a) obtaining, providing, or generating a library comprising bacterial cells or beads comprising a plurality of tumor antigens, wherein each bacterial cell or bead of the library comprises a different tumor antigen;
b) contacting the bacterial cells or beads with antigen presenting cells (APCs) from a subject, wherein the APCs internalize the bacterial cells or beads;
c) contacting the APCs with lymphocytes from the subject, under conditions suitable for activation of lymphocytes by a tumor antigen presented by one or more APCs;
d) determining whether one or more lymphocytes are activated by one or more tumor antigens presented by one or more APCs by assessing a level of expression and/or secretion of one or more immune mediators;
e) identifying each activating tumor antigen as (i) an antigen that stimulates the level of expression and/or secretion of one or more immune mediators, or (ii) an antigen that inhibits and/or suppresses the level of expression and/or secretion of one or more immune mediators, to obtain or generate a subject response profile; and
2) determining, based on one or more characteristics of the subject response profile, whether the subject is a candidate subject for initiation, continuation, modification, discontinuation or non-initiation of a cancer therapy.
294 . The method of claim 293 , wherein the subject response profile comprises a representation of the level of expression and/or secretion of the one or more immune mediators associated with the plurality of tumor antigens.
295 . The method of claim 293 , wherein the one or more characteristics of the subject response profile include:
(i) number of activating tumor antigens identified;
(ii) number of antigens that stimulate the level of expression and/or secretion of one or more immune mediators; and/or
(iii) number of antigens that inhibit and/or suppress the level of expression and/or secretion of one or more immune mediators.
296 . The method of claim 293 , wherein the subject response profile is in the form of a report in paper and/or electronic form.
297 . The method of claim 293 , wherein the report also contains information on prognosis, resistance, or potential or suggested therapeutic options; information on the likely effectiveness of a therapeutic option; the acceptability of a therapeutic option; the advisability of applying the therapeutic option to a cancer patient; and/or a recommendation on the administration of a cancer therapy (e.g., the administration of a pre-selected dosage or in a preselected treatment regimen e.g., in combination with one or more alternative cancer therapies).
298 . The method of claim 293 , wherein the subject suffers from a tumor.
299 . The method of claim 298 , wherein the tumor is or comprises a solid tumor selected from a breast carcinoma, a squamous cell carcinoma, a colon cancer, a head and neck cancer, ovarian cancer, a lung cancer, mesothelioma, a genitourinary cancer, a rectal cancer, a gastric cancer, or an esophageal cancer.
300 . The method of claim 293 , wherein the cancer therapy comprises an immunogenic composition comprising: (i) one or more antigens that increase a level of expression and/or secretion of one or more immune mediators associated with at least one beneficial response to cancer, and/or (ii) one or more tumor antigens that inhibit and/or suppress a level of expression and/or secretion of one or more immune mediators associated with at least one deleterious and/or non-beneficial response to cancer, or immunogenic fragments thereof.
301 . The method of claim 293 , wherein the cancer therapy further comprises at least one immune checkpoint inhibitor.
302 . The method of claim 293 , wherein the immunogenic composition does not comprise (iii) one or more tumor antigens that increase level of expression and/or secretion of one or more immune mediators associated with at least one deleterious and/or non-beneficial response to cancer, and/or (iv) one or more tumor antigens that inhibit and/or suppress level of expression and/or secretion of one or more immune mediators associated with at least one beneficial response to cancer, or immunogenic fragments thereof.