Methods and systems for determining personalized t'herapies
A method for generating an immune score, the method comprising the steps of: (i) determining a qualitative and/or quantitative assessment of tumor infiltrating lymphocytes in a sample; (ii) determining a qualitative and/or quantitative assessment of T-cell receptor signaling in the sample; (iii) determining a qualitative and/or quantitative assessment of mutation burden in the sample; (iv) generating, using a predictive algorithm, an immune score based on the determined qualitative and/or quantitative assessment of tumor infiltrating lymphocytes, the determined qualitative and/or quantitative assessment of T-cell receptor signaling, and the determined qualitative and/or quantitative assessment of mutation burden.
1. A method for analyzing a patient's tumor, the method comprising the steps of:
determining a qualitative and/or quantitative assessment of tumor infiltrating lymphocytes in a sample from the tumor, comprising determining mRNA expression of a plurality of genes associated with tumor infiltrating lymphocytes;
determining a qualitative and/or quantitative assessment of T-cell receptor signaling in the sample, comprising determining mRNA expression of a plurality of T-cell receptor signaling genes (TCRS) associated with anti-cancer immune response and/or immunotherapeutic targets;
determining a qualitative and/or quantitative assessment of mutational burden in the sample, comprising DNA sequencing and analysis of the sample;
classifying, based on the determined qualitative and/or quantitative assessment of tumor infiltrating lymphocytes, the determined qualitative and/or quantitative assessment of T-cell receptor signaling, and the determined qualitative and/or quantitative assessment of mutational burden, the sample as a responder to a therapy;
determining a response of the tumor, based on classifying the sample as a responder to a therapy, to one or more possible treatment therapies; and
administering the determined one or more possible treatment therapies to the patient.
2. The method of claim 1 , wherein the treatment is an immune checkpoint blockade therapy for the tumor.
3. The method of claim 2 , wherein the immune checkpoint blockade therapy is ipilimumab or a similar drug.
4. The method of claim 1 , further comprising the step of correlating the determined classification of the sample with a second classification.
5. The method of claim 4 , further comprising the step of determining a response of the tumor, based on the correlation, to one or more possible treatment therapies.
6. The method of claim 1 , further comprising the step of determining immunohistochemistry data for the sample, wherein said classifying step is further based on the determined immunohistochemistry data.
7. The method of claim 1 , wherein the plurality of genes associated with tumor infiltrating lymphocytes comprises at least CD163, CD2, CD3D, CD3E, CD3G, CD4, CD68, CD8A, CD8B, FOXP3 and CD20.
8. The method of claim 1 , wherein the plurality of genes associated with tumor infiltrating lymphocytes consists of CD163, CD2, CD3D, CD3E, CD3G, CD4, CD68, CD8A, CD8B, FOXP3 and CD20.
9. The method of claim 1 , wherein the plurality of genes associated with tumor infiltrating lymphocytes, and/or the plurality of T-cell receptor signaling genes associated with anti-cancer immune response and/or immunotherapeutic targets, consists of CD163, CD2, CD3D, CD3E, CD3G, CD4, CD68, CD8A, CD8B, FOXP3 and CD20.
10. The method of claim 1 , wherein the plurality of T-cell receptor signaling genes associated with anti-cancer immune response and/or immunotherapeutic targets comprises the 43 TCRS genes listed in
TABLE 1
Genes Utilized for an Embodiment of the 54 Gene Model
TILs
Genes
(11)
TCRS Genes (43)
CD163
ADORA2A
CD40LG
TIM3
PD-L2
CD2
BTLA
CD80 (B7-1)
ICOS
STAT1
CD3D
VISTA (B7-H5)
CD86 (B7-2)
ICOSLG
TBX21
CD3E
CCL2
CSF1R
IDO1
TGFB1
CD3G
CCR2
CTLA4
IFNG
TNF
CD4
SLAMF4
CXCL10
IL10
TNFRSF14
CD68
CD27 (TNFRSF27)
CXCR6
IL1B
GITR
CD8A
PD-L1
DDX58
KLRD1
OX40
CD8B
CD28
ENTPD1
LAG3
CD137
FOXP3
CD38
GATA3
MX1
OX-40L
CD20
CD40
GZMB
PD-1.
11. The method of claim 1 , wherein the plurality of T-cell receptor signaling genes associated with anti-cancer immune response and/or immunotherapeutic targets consists of the 43 TCRS genes listed in
TABLE 1
Genes Utilized for an Embodiment of the 54 Gene Model
TILs
Genes
(11)
TCRS Genes (43)
CD163
ADORA2A
CD40LG
TIM3
PD-L2
CD2
BTLA
CD80 (B7-1)
ICOS
STAT1
CD3D
VISTA (B7-H5)
CD86 (B7-2)
ICOSLG
TBX21
CD3E
CCL2
CSF1R
IDO1
TGFB1
CD3G
CCR2
CTLA4
IFNG
TNF
CD4
SLAMF4
CXCL10
IL10
TNFRSF14
CD68
CD27 (TNFRSF27)
CXCR6
IL1B
GITR
CD8A
PD-L1
DDX58
KLRD1
OX40
CD8B
CD28
ENTPD1
LAG3
CD137
FOXP3
CD38
GATA3
MX1
OX-40L
CD20
CD40
GZMB
PD-1.
12. The method of claim 1 , wherein the plurality of T-cell receptor signaling genes associated with anti-cancer immune response and/or immunotherapeutic targets, and/or the plurality of genes associated with tumor infiltrating lymphocytes, comprises at least some of the genes listed in
TABLE 1
Genes Utilized for an Embodiment of the 54 Gene Model
TILs
Genes
(11)
TCRS Genes (43)
CD163
ADORA2A
CD40LG
TIM3
PD-L2
CD2
BTLA
CD80 (B7-1)
ICOS
STAT1
CD3D
VISTA (B7-H5)
CD86 (B7-2)
ICOSLG
TBX21
CD3E
CCL2
CSF1R
IDO1
TGFB1
CD3G
CCR2
CTLA4
IFNG
TNF
CD4
SLAMF4
CXCL10
IL10
TNFRSF14
CD68
CD27 (TNFRSF27)
CXCR6
IL1B
GITR
CD8A
PD-L1
DDX58
KLRD1
OX40
CD8B
CD28
ENTPD1
LAG3
CD137
FOXP3
CD38
GATA3
MX1
OX-40L
CD20
CD40
GZMB
PD-1.
13. The method of claim 1 , wherein the plurality of T-cell receptor signaling genes associated with anti-cancer immune response and/or immunotherapeutic targets, and/or the plurality of genes associated with tumor infiltrating lymphocytes, comprises the genes listed in
TABLE 1
Genes Utilized for an Embodiment of the 54 Gene Model
TILs
Genes
(11)
TCRS Genes (43)
CD163
ADORA2A
CD40LG
TIM3
PD-L2
CD2
BTLA
CD80 (B7-1)
ICOS
STAT1
CD3D
VISTA (B7-H5)
CD86 (B7-2)
ICOSLG
TBX21
CD3E
CCL2
CSF1R
IDO1
TGFB1
CD3G
CCR2
CTLA4
IFNG
TNF
CD4
SLAMF4
CXCL10
IL10
TNFRSF14
CD68
CD27 (TNFRSF27)
CXCR6
IL1B
GITR
CD8A
PD-L1
DDX58
KLRD1
OX40
CD8B
CD28
ENTPD1
LAG3
CD137
FOXP3
CD38
GATA3
MX1
OX-40L
CD20
CD40
GZMB
PD-1.
14. The method of claim 1 , wherein the DNA sequencing and analysis of the sample comprises whole or partial exome sequencing.
15. The method of claim 1 , wherein the DNA sequencing and analysis of the sample comprises whole genome sequencing.
16. The method of claim 1 , wherein the mutational burden in the sample is a number of mutations per megabase of DNA.
17. The method of claim 16 , wherein the determined mutational burden is classified based on comparison to a reference population.
18. The method of claim 17 , wherein the determined mutational burden is classified as one of: (1) very high; (2) high; (3) intermediate; (4) low; and (5) very low based on said comparison.
19. The method of claim 1 , wherein classifying the sample as a responder to a therapy comprises a Bayesian Model Averaging of the determined qualitative and/or quantitative assessment of tumor infiltrating lymphocytes, the determined qualitative and/or quantitative assessment of T-cell receptor signaling, and the determined qualitative and/or quantitative assessment of mutational burden.