Systems and methods for predicting therapy efficacy from normalized biomarker scores
Techniques for determining therapy scores for at least two of an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy. The techniques include determining, using sequencing data for the subject and information indicating distribution of biomarker values across one or more reference populations, a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy; providing the first set of normalized biomarker scores as input to a statistical model to obtain a first therapy score for the first therapy; and providing the second set of normalized biomarker scores as input to the statistical model to obtain a second therapy score for the second therapy.
1. A system, comprising:
at least one computer hardware processor; and
at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform:
obtaining sequencing data about at least one biological sample of a subject;
accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers, each biomarker in the reference subset of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies, the reference subset of the plurality of biomarkers including a first biomarker and a second biomarker, and the biomarker information including a first distribution of values for the first biomarker and a second distribution of values for the second biomarker;
determining, using both the sequencing data and the biomarker information, therapy scores for at least some therapies in the plurality of therapies, the determining comprising:
determining, using the sequencing data, a first set of un-normalized biomarker scores for a first set of biomarkers in the reference subset of the plurality of biomarkers, the first set of un-normalized biomarker scores including a first un-normalized biomarker score for the first biomarker and a second un-normalized biomarker score for the second biomarker, and the first set of biomarkers being associated with a first therapy in the at least some therapies;
determining a first set of normalized biomarker scores for the first set of biomarkers, the first set of normalized biomarker scores including a first normalized biomarker score for the first biomarker and a second normalized biomarker score for the second biomarker, and the determining comprising:
adjusting the first set of un-normalized biomarker scores for the first set of biomarkers to a common scale, the adjusting comprising adjusting the first and second un-normalized biomarker scores to the common scale using the first and second distributions of values respectively; and
determining a first therapy score for the first therapy using the first set of normalized biomarker scores,
wherein the first therapy is selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy, and
wherein the first set of biomarkers comprises at least three biomarkers selected from the group of biomarkers associated with the first therapy in Table 2; and
recommending, for the subject, at least one therapy of the at least some therapies based on the determined therapy scores,
wherein the Table 2 is:
Therapy
Biomarkers
aPD1
Affinity of
AXL
B2M LOF mutation
BRAF mutation
therapy
neontigens
BRCA2 mutation
Cancer gene panels
Cancer gene panels
CCL13
(CGPs) FM-CGP
(CGPs) HSL-CGP
CCL2
CCL7
CCL8
CD8+ cell density in
the tumor invasive
margin
CD8+ cell number
CDH1
CVEGFC
CX3CL1 expression
CXCR2 expression
Dendritic cell number
EGFR expression
Endothelial cells
Eosinophil number
ESRP1 expression
Fibroblasts
Granzyme B
expression
JAK1 LOF mutation
JAK2 LOF mutation
LDH level
Lymphocyte number
M1 macrophage
M1/M2 macrophage
MDSC %
MHC-II expression
number
ratio
MHC-II expression
Missmatch-repair
MITF expression
Mutational Burden
(HLA-DRA)
deficiency status
Pattern of distant
PD-L1 expression
PD-L1 expression on
PTEN loss
metastases
infiltrating leukocytes
Quantity of
ROR2
STAT1 expression
T reg cell %
neoantigen peptides
TAGLN
TCR clonality
TGFbeta level
TIL number in
tumor
TWIST2
VEGF level
VEGFA
aCTLA4
Absolute
CD8+ cell number
CXCL11 expression
CXCL9 expression
therapy
lymphocyte count
CXCR3 expression
Dendritic cell number
EOMES+ CD8+ cells
FOXP3+ cells
number
number
IDO expression
LDH expression
M1 macrophage
M1/M2 macrophage
number
ratio
MDSC %
Mutational Burden
NY-ESO-1 seropostive
PTEN loss
T reg cell %
TCR clonality
TGFbeta level
TIL number in
tumor
VEGF level
IL-2 therapy
Bone metastasis
concomitant regional
Leucocytes number
LNPEP expression
lymphadenopathy
C-reactive protein
Delta32 CCR5
BCAT2 expression
BDNFOS
level
Polymorphism
expression
IL-10 (−1082G -> A)
CAIX expression
LOC130576
CCR5 LOF
polymorphism
expression
mutation
ERCC1 (codon 118)
IFN-g (+874A -> T)
LOC399900
ATP6V0A2
polymorphism
polymorphism
expression
expression
Ki-67 expression
Alkaline phosphatase
ARHGAP10
CD56+ or CD57+
level
expression
cells number
Liver metastasis
CD83+ TIDC cells
CDNA FLJ37989
LDH level
number
expression
Fibronectin level
HLA-DQB1
GBF1 expression
amount of alveolar
expression
component
Albumin level
clear cell
FOXP3+ cells number
HLA-DQA1
histology
expression
granular features
MAP3K5 expression
MDSC number
Mediastinum
metastasis
MEF2A expression
MTUS1 expression
Neutrophil number
NK cell number
non clear cell
NR1H2 expression
NRAS mutations
Number of
histology
metastatic sites
papillary features
PH-4 expression
Platelets Number
RABL2B
expression
RC3H2 expression
rs12553173
Sedimentation rate
SUPT6H
expression
TACC1 expression
TDP1 expression
TFPI expression
Time from tumor to
occurrence of
metastases
Transferrin level
TSH level
VCAM1 expression
VEGF level
Weight loss
α-antitrypsin level
IFNa
CAIX level
Delta32 CCR5
Leucocytes count
LNPEP expression
therapy
Polymorphism
ERCC1 (codon 118)
GBF1 expression
Bone metastasis
Breslow thickness
polymorphism
IL-6 expression
CCR5 LOF mutation
LOC130576
CD4+ cells number
level
expression
Hepatic RIG-1
IL-1β expression
LOC399900
BDNFOS
expression
level
expression
expression
Interval from initial
ARHGAP10
BCAT2 expression
CD8+ CD57+ cells
diagnosis to
expression
number
treatment
Liver metastasis
CD83+ TIDC cells
CDNA FLJ37989 fis
Ki-67 expression
number
expression
HLA-Cw06 allele
IL-1α expression
HLA-DQB1
ATP6V0A2
level
expression
expression
Alkaline
collagen IV level
HLA-DQA1
IL-10 (−1082G -> A)
phosphatase level
expression
polymorphism
IFN-g (+874A -> T)
MAP3K5 expression
Mediastinum metastasis
MEF2A expression
polymorphism
MIP-1α expression
MIP-1β expression
MTAP gene expression
MTUS1 expression
level
level
Neutrophil count
NR1H2 expression
Number of metastatic
Osteopontin level
sites
Performance status
PH-4 expression
Platelets Number
RABL2B
expression
RC3H2 expression
Sedimentation rate
Serum calcium level
Serum hemoglobin
level
STAT1 gene
SUPT6H expression
TACC1 expression
TDP1 expression
expression
TFPI expression
Time from tumor to
TNF-α expression level
TRAIL level
occurrence of
metastases
Ulceration of
VCAM1 expression
VEGF level
VEGFR2 level
primary
Anti-cancer
Cancer-Testis
CD16+ CD56+
CD4+ CD45RO+ cell
CD4+ CTLA-4+
vaccine
Antigens' Genes
CD69+ lymphocytes
number
T cell number
therapy
expression
number
CD4+ PD-1+ T cell
C-reactive protein
ECOG performance
EGF level
number
level
score
I/II high-grade or III
IFN-gamma-induced
IgM for Blood Group A
IL-6 level
T1/2/3a low-grade
tumor cell apoptosis
trisaccharide level
disease intermediate
risk
Intratumoral versus
LDH level
Lin-CD14+ HLA-DR−/
lymphocyte number
peritumoral T cell
lo MDSC level
density
lymphocytes in
M1/M2 macrophage
MDSC number
Mean Corpuscular
PBMC %
ratio
Hemoglobin
Concentration
(MCHC)
Number of CD27−
Patient's age
Predictive gene
PTEN loss
CD45RA+ and
signature in MAGE A3
CD27− CD45RA−
antigen-specific cancer
and
immunotherapy
CD27+ CD45RA−
T-cells
Serum amyloid A
Serum S100B
Syndecan-4 mRNA
T reg cell %
level
concentration
expression level
TGFbeta level
Toll-like receptor 4
WT1 expression
gene polymorphism
Anti-
Acneiform rash
Adrenomedullin
angiopoietin-2
Bioactive Peptide
angiogenic
Repeat
expression levels
Induced Signaling
therapy
Polymorphism
Pathway
CD133 expression
CDC16 level
Child-Pugh class
CXCL10 plasma
level
CXCR1 rs2234671
CXCR2 C785T
CXCR2 rs2230054
ECOG Performance
G > C
T > C
Status
EGF A-61G
EGF rs444903 A > G
EGFR expression levels
EGFR rs2227983
G > A
Endothelin-1
Expression of CD31
Expression of
HBV status
expression levels
PDGFR-beta
HGF plasma level
History of alcohol
ICAM1 T469C
IFN-α2 plasma level
intake
IGF-1 rs6220 A > G
IL-12 plasma level
IL-16 plasma level
IL-2Rα plasma level
IL-3 plasma level
IL-6 plasma level
IL-8 251 T > A
IL-8 plasma level
Lck and Fyn
Liver metastasis
M-CSF plasma level
mucinous histology
tyrosine kinases in
initiation of TCR
Activation pathway
activation
NO2-dependent IL
Number of resting
Number of total
PIGF plasma level
12 Pathway
circulating
circulating endothelial
activation in NK
endothelial cells
cells
cells
portal vein
rs12505758 in
rs2286455
rs3130
thrombosis
VEGFR2
rs699946 in VEGFA
SDF-1α plasma level
Sex
sVEGFR1
T Cell Receptor
T Helper Cell Surface
TRAIL plasma level
VEGF-1154 A > G
Signaling Pathway
Molecules expression
activation
VEGF-1498 C > T
VEGF C936T
VEGF G-634C
VEGF-1154 G/A
VEGF-2578 C/A
VEGFR1 rs9582036
VEGFR-2 rs2305948
WNK1-rs11064560
C > T
Rituximab
BCL2 expression
BCL6 expression
Beclin-1 expression
ClqA Gene
level
Polymorphism
Carbohydrate
CD163-positive
CD20 expression
CD37 expression
antigen-125 level
macrophages
level
CD5 expression
CXCR4 expression
Cytotoxic T
FcγRIIIa 158H/H
level
level
lymphocyte-associated
genotypes
Granzyme B expression
level
Galectin-1
HIP1R mRNA level
IL-12 level
IL-1RA level
expression
Ki-67 expression
MARCO expression
Mast cell number 1
miR-155 expression
MYC expression
Number of
p21 protein expression
SLR11 level
macrophages
SMAD1 expression
STAT3
T cells
TAM number
mRNA level
TIM3 expression.
2. The system of claim 1 , wherein the processor-executable instructions further cause the at least one computer hardware processor to perform:
determining, using both the sequencing data and the biomarker information, a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies; and
determining a second therapy score using the second set of normalized biomarker scores.
3. The system of claim 1 , wherein determining the first therapy score for the first therapy is performed using a statistical model selected from the group consisting of a linear model, a generalized linear model, a neural network model, a Bayesian regression model, an adaptive non-linear regression model, a mixture model, and a random forest regression model.
4. The system of claim 1 , wherein determining the first normalized biomarker score comprises:
determining the first un-normalized biomarker score for the first biomarker using the sequencing data;
determining a Z-score based on the first distribution of values for the first biomarker; and
determining the first normalized biomarker score for the first biomarker based on the first un-normalized biomarker score and the Z-score.
5. The system of claim 1 , wherein determining the first therapy score comprises:
determining weights for two or more scores in the first set of normalized biomarker scores for the subject; and
determining the first therapy score as a sum of the two or more scores, summands of the sum being weighted by the determined weights.
6. The system of claim 1 , wherein the first therapy score is indicative of response of the subject to administration of the first therapy.
7. The system of claim 1 , wherein the sequencing data comprises RNA sequencing data.
8. At least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform:
obtaining sequencing data about at least one biological sample of a subject;
accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers, each biomarker in the reference subset of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies, the reference subset of the plurality of biomarkers including a first biomarker and a second biomarker, and the biomarker information including a first distribution of values for the first biomarker and a second distribution of values for the second biomarker;
determining, using both the sequencing data and the biomarker information, therapy scores for at least some therapies in the plurality of therapies, the determining comprising:
determining, using the sequencing data, a first set of un-normalized biomarker scores for a first set of biomarkers in the reference subset of the plurality of biomarkers, the first set of un-normalized biomarker scores including a first un-normalized biomarker score for the first biomarker and a second un-normalized biomarker score for the second biomarker, and the first set of biomarkers being associated with a first therapy in the at least some therapies;
determining a first set of normalized biomarker scores for the first set of biomarkers, the first set of normalized biomarker scores including a first normalized biomarker score for the first biomarker and a second normalized biomarker score for the second biomarker, and the determining comprising:
adjusting the first set of un-normalized biomarker scores for the first set of biomarkers to a common scale, the adjusting comprising adjusting the first and second un-normalized biomarker scores to the common scale using the first and second distributions of values respectively; and
determining a first therapy score for the first therapy using the first set of normalized biomarker scores,
wherein the first therapy is selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy, and
wherein the first set of biomarkers comprises at least three biomarkers selected from the group of biomarkers associated with the first therapy in Table 2; and
recommending, for the subject, at least one therapy of the at least some therapies based on the determined therapy scores,
wherein the Table 2 is:
Therapy
Biomarkers
aPD1
Affinity of
AXL
B2M LOF mutation
BRAF mutation
therapy
neontigens
BRCA2 mutation
Cancer gene panels
Cancer gene panels
CCL13
(CGPs) FM-CGP
(CGPs) HSL-CGP
CCL2
CCL7
CCL8
CD8+ cell density in
the tumor invasive
margin
CD8+ cell number
CDH1
CVEGFC
CX3CL1 expression
CXCR2 expression
Dendritic cell number
EGFR expression
Endothelial cells
Eosinophil number
ESRP1 expression
Fibroblasts
Granzyme B
expression
JAK1 LOF mutation
JAK2 LOF mutation
LDH level
Lymphocyte number
M1 macrophage
M1/M2 macrophage
MDSC %
MHC-II expression
number
ratio
MHC-II expression
Missmatch-repair
MITF expression
Mutational Burden
(HLA-DRA)
deficiency status
Pattern of distant
PD-L1 expression
PD-L1 expression on
PTEN loss
metastases
infiltrating leukocytes
Quantity of
ROR2
STAT1 expression
T reg cell %
neoantigen peptides
TAGLN
TCR clonality
TGFbeta level
TIL number in
tumor
TWIST2
VEGF level
VEGFA
aCTLA4
Absolute
CD8+ cell number
CXCL11 expression
CXCL9 expression
therapy
lymphocyte count
CXCR3 expression
Dendritic cell number
EOMES+ CD8+ cells
FOXP3+ cells
number
number
IDO expression
LDH expression
M1 macrophage
M1/M2 macrophage
number
ratio
MDSC %
Mutational Burden
NY-ESO-1 seropostive
PTEN loss
T reg cell %
TCR clonality
TGFbeta level
TIL number in
tumor
VEGF level
IL-2 therapy
Bone metastasis
concomitant regional
Leucocytes number
LNPEP expression
lymphadenopathy
C-reactive protein
Delta32 CCR5
BCAT2 expression
BDNFOS
level
Polymorphism
expression
IL-10 (−1082G -> A)
CAIX expression
LOC130576
CCR5 LOF
polymorphism
expression
mutation
ERCC1 (codon 118)
IFN-g (+874A -> T)
LOC399900
ATP6V0A2
polymorphism
polymorphism
expression
expression
Ki-67 expression
Alkaline phosphatase
ARHGAP10
CD56+ or CD57+
level
expression
cells number
Liver metastasis
CD83+ TIDC cells
CDNA FLJ37989
LDH level
number
expression
Fibronectin level
HLA-DQB1
GBF1 expression
amount of alveolar
expression
component
Albumin level
clear cell
FOXP3+ cells number
HLA-DQA1
histology
expression
granular features
MAP3K5 expression
MDSC number
Mediastinum
metastasis
MEF2A expression
MTUS1 expression
Neutrophil number
NK cell number
non clear cell
NR1H2 expression
NRAS mutations
Number of
histology
metastatic sites
papillary features
PH-4 expression
Platelets Number
RABL2B
expression
RC3H2 expression
rs12553173
Sedimentation rate
SUPT6H
expression
TACC1 expression
TDP1 expression
TFPI expression
Time from tumor to
occurrence of
metastases
Transferrin level
TSH level
VCAM1 expression
VEGF level
Weight loss
α-antitrypsin level
IFNa
CAIX level
Delta32 CCR5
Leucocytes count
LNPEP expression
therapy
Polymorphism
ERCC1 (codon 118)
GBF1 expression
Bone metastasis
Breslow thickness
polymorphism
IL-6 expression
CCR5 LOF mutation
LOC130576
CD4+ cells number
level
expression
Hepatic RIG-1
IL-1β expression
LOC399900
BDNFOS
expression
level
expression
expression
Interval from initial
ARHGAP10
BCAT2 expression
CD8+ CD57+ cells
diagnosis to
expression
number
treatment
Liver metastasis
CD83+ TIDC cells
CDNA FLJ37989 fis
Ki-67 expression
number
expression
HLA-Cw06 allele
IL-1α expression
HLA-DQB1
ATP6V0A2
level
expression
expression
Alkaline
collagen IV level
HLA-DQA1
IL-10 (−1082G -> A)
phosphatase level
expression
polymorphism
IFN-g (+874A -> T)
MAP3K5 expression
Mediastinum metastasis
MEF2A expression
polymorphism
MIP-1α expression
MIP-1β expression
MTAP gene expression
MTUS1 expression
level
level
Neutrophil count
NR1H2 expression
Number of metastatic
Osteopontin level
sites
Performance status
PH-4 expression
Platelets Number
RABL2B
expression
RC3H2 expression
Sedimentation rate
Serum calcium level
Serum hemoglobin
level
STAT1 gene
SUPT6H expression
TACC1 expression
TDP1 expression
expression
TFPI expression
Time from tumor to
TNF-α expression level
TRAIL level
occurrence of
metastases
Ulceration of
VCAM1 expression
VEGF level
VEGFR2 level
primary
Anti-cancer
Cancer-Testis
CD16+ CD56+
CD4+ CD45RO+ cell
CD4+ CTLA-4+
vaccine
Antigens' Genes
CD69+ lymphocytes
number
T cell number
therapy
expression
number
CD4+ PD-1+ T cell
C-reactive protein
ECOG performance
EGF level
number
level
score
I/II high-grade or III
IFN-gamma-induced
IgM for Blood Group A
IL-6 level
T1/2/3a low-grade
tumor cell apoptosis
trisaccharide level
disease intermediate
risk
Intratumoral versus
LDH level
Lin-CD14+ HLA-DR−/
lymphocyte number
peritumoral T cell
lo MDSC level
density
lymphocytes in
M1/M2 macrophage
MDSC number
Mean Corpuscular
PBMC %
ratio
Hemoglobin
Concentration
(MCHC)
Number of CD27−
Patient's age
Predictive gene
PTEN loss
CD45RA+ and
signature in MAGE A3
CD27− CD45RA−
antigen-specific cancer
and
immunotherapy
CD27+ CD45RA−
T-cells
Serum amyloid A
Serum S100B
Syndecan-4 mRNA
T reg cell %
level
concentration
expression level
TGFbeta level
Toll-like receptor 4
WT1 expression
gene polymorphism
Anti-
Acneiform rash
Adrenomedullin
angiopoietin-2
Bioactive Peptide
angiogenic
Repeat
expression levels
Induced Signaling
therapy
Polymorphism
Pathway
CD133 expression
CDC16 level
Child-Pugh class
CXCL10 plasma
level
CXCR1 rs2234671
CXCR2 C785T
CXCR2 rs2230054
ECOG Performance
G > C
T > C
Status
EGF A-61G
EGF rs444903 A > G
EGFR expression levels
EGFR rs2227983
G > A
Endothelin-1
Expression of CD31
Expression of
HBV status
expression levels
PDGFR-beta
HGF plasma level
History of alcohol
ICAM1 T469C
IFN-α2 plasma level
intake
IGF-1 rs6220 A > G
IL-12 plasma level
IL-16 plasma level
IL-2Rα plasma level
IL-3 plasma level
IL-6 plasma level
IL-8 251 T > A
IL-8 plasma level
Lck and Fyn
Liver metastasis
M-CSF plasma level
mucinous histology
tyrosine kinases in
initiation of TCR
Activation pathway
activation
NO2-dependent IL
Number of resting
Number of total
PIGF plasma level
12 Pathway
circulating
circulating endothelial
activation in NK
endothelial cells
cells
cells
portal vein
rs12505758 in
rs2286455
rs3130
thrombosis
VEGFR2
rs699946 in VEGFA
SDF-1α plasma level
Sex
sVEGFR1
T Cell Receptor
T Helper Cell Surface
TRAIL plasma level
VEGF-1154 A > G
Signaling Pathway
Molecules expression
activation
VEGF-1498 C > T
VEGF C936T
VEGF G-634C
VEGF-1154 G/A
VEGF-2578 C/A
VEGFR1 rs9582036
VEGFR-2 rs2305948
WNK1-rs11064560
C > T
Rituximab
BCL2 expression
BCL6 expression
Beclin-1 expression
C1qA Gene
level
Polymorphism
Carbohydrate
CD163-positive
CD20 expression
CD37 expression
antigen-125 level
macrophages
level
CD5 expression
CXCR4 expression
Cytotoxic T
FcγRIIIa 158H/H
level
level
lymphocyte-associated
genotypes
Granzyme B expression
level
Galectin-1
HIP1R mRNA level
IL-12 level
IL-1RA level
expression
Ki-67 expression
MARCO expression
Mast cell number 1
miR-155 expression
MYC expression
Number of
p21 protein expression
SLR11 level
macrophages
SMAD1 expression
STAT3
T cells
TAM number
mRNA level
TIM3 expression.
9. The at least one non-transitory computer-readable storage medium of claim 8 , wherein the processor-executable instructions further cause the at least one computer hardware processor to perform:
determining, using both the sequencing data and the biomarker information, a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies; and
determining a second therapy score using the second set of normalized biomarker scores.
10. The at least one non-transitory computer-readable storage medium of claim 8 , wherein determining the first therapy score for the first therapy is performed using a statistical model selected from the group consisting of a linear model, a generalized linear model, a neural network model, a Bayesian regression model, an adaptive non-linear regression model, a mixture model, and a random forest regression model.
11. The at least one non-transitory computer-readable storage medium of claim 8 , wherein determining the first normalized biomarker score comprises:
determining the first un-normalized biomarker score for the first biomarker using the sequencing data;
determining a Z-score based on the first distribution of values for the first biomarker; and
determining the first normalized biomarker score for the first biomarker based on the first un-normalized biomarker score and the Z-score.
12. The at least one non-transitory computer-readable storage medium of claim 8 , wherein determining the first therapy score comprises:
determining weights for two or more scores in the first set of normalized biomarker scores for the subject; and
determining the first therapy score as a sum of the two or more scores, summands of the sum being weighted by the determined weights.
13. The at least one non-transitory computer-readable storage medium of claim 8 , wherein the first therapy score is indicative of response of the subject to administration of the first therapy.
14. The at least one non-transitory computer-readable storage medium of claim 8 , wherein the sequencing data comprises RNA sequencing data.
15. A method, comprising:
using at least one computer hardware processor to perform:
obtaining sequencing data about at least one biological sample of a subject;
accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers, each biomarker in the reference subset of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies, the reference subset of the plurality of biomarkers including a first biomarker and a second biomarker, and the biomarker information including a first distribution of values for the first biomarker and a second distribution of values for the second biomarker;
determining, using both the sequencing data and the biomarker information, therapy scores for at least some therapies in the plurality of therapies, the determining comprising:
determining, using the sequencing data, a first set of un-normalized biomarker scores for a first set of biomarkers in the reference subset of the plurality of biomarkers, the first set of un-normalized biomarker scores including a first un-normalized biomarker score for the first biomarker and a second un-normalized biomarker score for the second biomarker, and the first set of biomarkers being associated with a first therapy in the at least some therapies;
determining a first set of normalized biomarker scores for the first set of biomarkers, the first set of normalized biomarker scores including a first normalized biomarker score for the first biomarker and a second normalized biomarker score for the second biomarker, and the determining comprising:
adjusting the first set of un-normalized biomarker scores for the first set of biomarkers to a common scale, the adjusting comprising adjusting the first and second un-normalized biomarker scores to the common scale using the first and second distributions of values respectively; and
determining a first therapy score for the first therapy using the first set of normalized biomarker scores,
wherein the first therapy is selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy, and
wherein the first set of biomarkers comprises at least three biomarkers selected from the group of biomarkers associated with the first therapy in Table 2; and
recommending, for the subject, at least one therapy of the at least some therapies based on the determined therapy scores,
wherein Table 2 is:
Therapy
Biomarkers
aPD1
Affinity of
AXL
B2M LOF mutation
BRAF mutation
therapy
neontigens
BRCA2 mutation
Cancer gene panels
Cancer gene panels
CCL13
(CGPs) FM-CGP
(CGPs) HSL-CGP
CCL2
CCL7
CCL8
CD8+ cell density in
the tumor invasive
margin
CD8+ cell number
CDH1
CVEGFC
CX3CL1 expression
CXCR2 expression
Dendritic cell number
EGFR expression
Endothelial cells
Eosinophil number
ESRP1 expression
Fibroblasts
Granzyme B
expression
JAK1 LOF mutation
JAK2 LOF mutation
LDH level
Lymphocyte number
M1 macrophage
M1/M2 macrophage
MDSC %
MHC-II expression
number
ratio
MHC-II expression
Missmatch-repair
MITF expression
Mutational Burden
(HLA-DRA)
deficiency status
Pattern of distant
PD-L1 expression
PD-L1 expression on
PTEN loss
metastases
infiltrating leukocytes
Quantity of
ROR2
STAT1 expression
T reg cell %
neoantigen peptides
TAGLN
TCR clonality
TGFbeta level
TIL number in
tumor
TWIST2
VEGF level
VEGFA
aCTLA4
Absolute
CD8+ cell number
CXCL11 expression
CXCL9 expression
therapy
lymphocyte count
CXCR3 expression
Dendritic cell number
EOMES+ CD8+ cells
FOXP3+ cells
number
number
IDO expression
LDH expression
M1 macrophage
M1/M2 macrophage
number
ratio
MDSC %
Mutational Burden
NY-ESO-1 seropostive
PTEN loss
T reg cell %
TCR clonality
TGFbeta level
TIL number in
tumor
VEGF level
IL-2 therapy
Bone metastasis
concomitant regional
Leucocytes number
LNPEP expression
lymphadenopathy
C-reactive protein
Delta32 CCR5
BCAT2 expression
BDNFOS
level
Polymorphism
expression
IL-10 (−1082G -> A)
CAIX expression
LOC130576
CCR5 LOF
polymorphism
expression
mutation
ERCC1 (codon 118)
IFN-g (+874A -> T)
LOC399900
ATP6V0A2
polymorphism
polymorphism
expression
expression
Ki-67 expression
Alkaline phosphatase
ARHGAP10
CD56+ or CD57+
level
expression
cells number
Liver metastasis
CD83+ TIDC cells
CDNA FLJ37989
LDH level
number
expression
Fibronectin level
HLA-DQB1
GBF1 expression
amount of alveolar
expression
component
Albumin level
clear cell
FOXP3+ cells number
HLA-DQA1
histology
expression
granular features
MAP3K5 expression
MDSC number
Mediastinum
metastasis
MEF2A expression
MTUS1 expression
Neutrophil number
NK cell number
non clear cell
NR1H2 expression
NRAS mutations
Number of
histology
metastatic sites
papillary features
PH-4 expression
Platelets Number
RABL2B
expression
RC3H2 expression
rs12553173
Sedimentation rate
SUPT6H
expression
TACC1 expression
TDP1 expression
TFPI expression
Time from tumor to
occurrence of
metastases
Transferrin level
TSH level
VCAM1 expression
VEGF level
Weight loss
α-antitrypsin level
IFNa
CAIX level
Delta32 CCR5
Leucocytes count
LNPEP expression
therapy
Polymorphism
ERCC1 (codon 118)
GBF1 expression
Bone metastasis
Breslow thickness
polymorphism
IL-6 expression
CCR5 LOF mutation
LOC130576
CD4+ cells number
level
expression
Hepatic RIG-1
IL-1β expression
LOC399900
BDNFOS
expression
level
expression
expression
Interval from initial
ARHGAP10
BCAT2 expression
CD8+ CD57+ cells
diagnosis to
expression
number
treatment
Liver metastasis
CD83+ TIDC cells
CDNA FLJ37989 fis
Ki-67 expression
number
expression
HLA-Cw06 allele
IL-1α expression
HLA-DQB1
ATP6V0A2
level
expression
expression
Alkaline
collagen IV level
HLA-DQA1
IL-10 (−1082G -> A)
phosphatase level
expression
polymorphism
IFN-g (+874A -> T)
MAP3K5 expression
Mediastinum metastasis
MEF2A expression
polymorphism
MIP-1α expression
MIP-1β expression
MTAP gene expression
MTUS1 expression
level
level
Neutrophil count
NR1H2 expression
Number of metastatic
Osteopontin level
sites
Performance status
PH-4 expression
Platelets Number
RABL2B
expression
RC3H2 expression
Sedimentation rate
Serum calcium level
Serum hemoglobin
level
STAT1 gene
SUPT6H expression
TACC1 expression
TDP1 expression
expression
TFPI expression
Time from tumor to
TNF-α expression level
TRAIL level
occurrence of
metastases
Ulceration of
VCAM1 expression
VEGF level
VEGFR2 level
primary
Anti-cancer
Cancer-Testis
CD16+ CD56+
CD4+ CD45RO+ cell
CD4+ CTLA-4+
vaccine
Antigens' Genes
CD69+ lymphocytes
number
T cell number
therapy
expression
number
CD4+ PD-1+ T cell
C-reactive protein
ECOG performance
EGF level
number
level
score
I/II high-grade or III
IFN-gamma-induced
IgM for Blood Group A
IL-6 level
T1/2/3a low-grade
tumor cell apoptosis
trisaccharide level
disease intermediate
risk
Intratumoral versus
LDH level
Lin-CD14+ HLA-DR−/
lymphocyte number
peritumoral T cell
lo MDSC level
density
lymphocytes in
M1/M2 macrophage
MDSC number
Mean Corpuscular
PBMC %
ratio
Hemoglobin
Concentration
(MCHC)
Number of CD27−
Patient's age
Predictive gene
PTEN loss
CD45RA+ and
signature in MAGE A3
CD27− CD45RA−
antigen-specific cancer
and
immunotherapy
CD27+ CD45RA−
T-cells
Serum amyloid A
Serum S100B
Syndecan-4 mRNA
T reg cell %
level
concentration
expression level
TGFbeta level
Toll-like receptor 4
WT1 expression
gene polymorphism
Anti-
Acneiform rash
Adrenomedullin
angiopoietin-2
Bioactive Peptide
angiogenic
Repeat
expression levels
Induced Signaling
therapy
Polymorphism
Pathway
CD133 expression
CDC16 level
Child-Pugh class
CXCL10 plasma
level
CXCR1 rs2234671
CXCR2 C785T
CXCR2 rs2230054
ECOG Performance
G > C
T > C
Status
EGF A-61G
EGF rs444903 A > G
EGFR expression levels
EGFR rs2227983
G > A
Endothelin-1
Expression of CD31
Expression of
HBV status
expression levels
PDGFR-beta
HGF plasma level
History of alcohol
ICAM1 T469C
IFN-α2 plasma level
intake
IGF-1 rs6220 A > G
IL-12 plasma level
IL-16 plasma level
IL-2Rα plasma level
IL-3 plasma level
IL-6 plasma level
IL-8 251 T > A
IL-8 plasma level
Lck and Fyn
Liver metastasis
M-CSF plasma level
mucinous histology
tyrosine kinases in
initiation of TCR
Activation pathway
activation
NO2-dependent IL
Number of resting
Number of total
PIGF plasma level
12 Pathway
circulating
circulating endothelial
activation in NK
endothelial cells
cells
cells
portal vein
rs12505758 in
rs2286455
rs3130
thrombosis
VEGFR2
rs699946 in VEGFA
SDF-1α plasma level
Sex
sVEGFR1
T Cell Receptor
T Helper Cell Surface
TRAIL plasma level
VEGF-1154 A > G
Signaling Pathway
Molecules expression
activation
VEGF-1498 C > T
VEGF C936T
VEGF G-634C
VEGF-1154 G/A
VEGF-2578 C/A
VEGFR1 rs9582036
VEGFR-2 rs2305948
WNK1-rs11064560
C > T
Rituximab
BCL2 expression
BCL6 expression
Beclin-1 expression
C1qA Gene
level
Polymorphism
Carbohydrate
CD163-positive
CD20 expression
CD37 expression
antigen-125 level
macrophages
level
CD5 expression
CXCR4 expression
Cytotoxic T
FcγRIIIa 158H/H
level
level
lymphocyte-associated
genotypes
Granzyme B expression
level
Galectin-1
HIP1R mRNA level
IL-12 level
IL-1RA level
expression
Ki-67 expression
MARCO expression
Mast cell number 1
miR-155 expression
MYC expression
Number of
p21 protein expression
SLR11 level
macrophages
SMAD1 expression
STAT3
T cells
TAM number
mRNA level
TIM3 expression.
16. The method of claim 15 , further comprising:
determining, using both the sequencing data and the biomarker information, a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies; and
determining a second therapy score using the second set of normalized biomarker scores.
17. The method of claim 15 , wherein determining the first therapy score for the first therapy is performed using a statistical model selected from the group consisting of a linear model, a generalized linear model, a neural network model, a Bayesian regression model, an adaptive non-linear regression model, a mixture model, and a random forest regression model.
18. The method of claim 15 , wherein determining the first normalized biomarker score comprises:
determining the first un-normalized biomarker score for the first biomarker using the sequencing data;
determining a Z-score based on the first distribution of values for the first biomarker; and
determining the first normalized biomarker score for the first biomarker based on the first un-normalized biomarker score and the Z-score.
19. The method of claim 15 , wherein determining the first therapy score comprises:
determining weights for two or more scores in the first set of normalized biomarker scores for the subject; and
determining the first therapy score as a sum of the two or more scores, summands of the sum being weighted by the determined weights.
20. The method of claim 15 , further comprising administering the first therapy to the subject.