Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of plasmid CXCL9 synergizes with plasmid IL-12 therapy to elicit robust anti-tumor immunity

Abstract

Clinical studies have demonstrated that local expression of the cytokine IL-12 drives interferon-gamma expression and recruits T cells to the tumor microenvironment, ultimately yielding durable systemic T cell responses. Interrogation of longitudinal biomarker data from our late-stage melanoma trials identified a significant on-treatment increase of intratumoral CXCR3 transcripts that was restricted to responding patients, underscoring the clinical relevance of tumor-infiltrating CXCR3+ immune cells. In this study, we sought to understand if the addition of DNA-encodable CXCL9 could augment the anti-tumor immune responses driven by intratumoral IL-12. We show that localized IL-12 and CXCL9 treatment reshapes the tumor microenvironment to promote dendritic cell licensing and CD8+ T cell activation. Additionally, this combination treatment results in a significant abscopal anti-tumor response and provides a concomitant benefit to anti-PD-1 therapies. Collectively, these data demonstrate that a functional tumoral CXCR3/CXCL9 axis is critical for IL-12 anti-tumor efficacy. Furthermore, restoring or amplifying the CXCL9 gradient in the tumors via intratumoral electroporation of plasmid CXCL9 can not only result in efficient trafficking of cytotoxic CD8+ T cells into the tumor but can also reshape the microenvironment to promote systemic immune response. Clinical studies have demonstrated that local expression of the cytokine IL-12 drives interferon-gamma expression and recruits T cells to the tumor microenvironment, ultimately yielding durable systemic T cell responses. Interrogation of longitudinal biomarker data from our late-stage melanoma trials identified a significant on-treatment increase of intratumoral CXCR3 transcripts that was restricted to responding patients, underscoring the clinical relevance of tumor-infiltrating CXCR3+ immune cells. In this study, we sought to understand if the addition of DNA-encodable CXCL9 could augment the anti-tumor immune responses driven by intratumoral IL-12. We show that localized IL-12 and CXCL9 treatment reshapes the tumor microenvironment to promote dendritic cell licensing and CD8+ T cell activation. Additionally, this combination treatment results in a significant abscopal anti-tumor response and provides a concomitant benefit to anti-PD-1 therapies. Collectively, these data demonstrate that a functional tumoral CXCR3/CXCL9 axis is critical for IL-12 anti-tumor efficacy. Furthermore, restoring or amplifying the CXCL9 gradient in the tumors via intratumoral electroporation of plasmid CXCL9 can not only result in efficient trafficking of cytotoxic CD8+ T cells into the tumor but can also reshape the microenvironment to promote systemic immune response. IntroductionThe overall tumor immune contexture characterized by the location, density, and functional organization of immune cells in the tumor microenvironment is widely recognized as an important determinant of clinical outcome.1Fridman W.H. Pagès F. Sautès-Fridman C. Galon J. The immune contexture in human tumours: impact on clinical outcome.Nat. Rev. Cancer. 2012; 12: 298-306https://doi.org/10.1038/nrc3245Google Scholar T cell inflamed tumors are often characterized by transcriptional profiles associated with T cell markers, pro-inflammatory cytokines, and chemokines. These profiles often correspond with clinical benefit to various immunotherapies, including checkpoint blockade and vaccines.2Gajewski T.F. Corrales L. Williams J. Horton B. Sivan A. Spranger S. Cancer immunotherapy targets based on understanding the T cell-inflamed versus non-T cell-inflamed tumor microenvironment.Adv. Exp. Med. Biol. 2017; 1036: 19-31https://doi.org/10.1007/978-3-319-67577-0_2Google Scholar,3Trujillo J.A. Sweis R.F. Bao R. Luke J.J. T cell–inflamed versus non-T cell–inflamed tumors: a conceptual framework for cancer immunotherapy drug development and combination therapy selection.Cancer Immunol. Res. 2018; 6: 990-1000https://doi.org/10.1158/2326-6066.cir-18-0277Google Scholar Several immune cells (MDSCs, TAMs, TANs, Tregs, suppressive B cells), endothelial cells, and stromal cells can infiltrate the tumor during its progression. These cells act to limit T cell function and trafficking via direct contact or secretion of suppressive molecules, rendering a poorly immunogenic tumor microenvironment (TME).4Kim R. Emi M. Tanabe of during Res. L. cells in tumor and therapy 12: M. associated in and S. C. cells that and are by Immunol. 2018; R. T cells and the suppressive tumor Immunol. A. J.A. A. B cell in cancer and anti-tumor Immunol. 2017; L. S. J. of the immune response by Immunol. 2018; Scholar that can this from a suppressive T to a T cell-inflamed are in and clinical cell trafficking is a the of and on T cells, to from the the expression of as These and from the in for and that are in the or are to the and to and to the microenvironment of of and and of an Immunol. Scholar Several studies have the of for T cell into the tumors and for associated anti-tumor A. A. B. The and of in tumor Immunol. 2012; in the cancer microenvironment and relevance in cancer Rev. Immunol. 2017; Scholar the of the axis is often a critical checkpoint that can a J. J.J. T.F. for CXCR3 during trafficking 6: and clinical studies have the of to the to promote anti-tumor J. J.J. T.F. for CXCR3 during trafficking 6: S. S. C. CXCR3 tumor by in a cancer J. J. M. of CXCR3 on tumor-infiltrating associated with in J. Exp. J. expression by CD8+ T cells is associated with in melanoma with Res. of CXCR3 on cells and CXCR3 in with cell in response to systemic Scholar Furthermore, have to important in efficient in and of T cells, including T cells by with J.A. of the CXCR3 is for the of anti-PD-1 J. L. CXCL9 and are for immune responses immune checkpoint Cancer Res. M. S. R. and T Scholar The axis and of immune cells. CXCR3 is on immune cell including T cells, CD8+ T cells, and S. The of CXCR3 and its in and Med. 2018; studies that interferon-gamma is a critical for intratumoral T cell via of its L. R. J. intratumoral expression of CXCL9 the local of T cells immunotherapy with Scholar and the of clinical response to anti-PD-1 including M. J. M. A. A. clinical response to 2017; Scholar We and have in clinical and that intratumoral expression of pro-inflammatory as IL-12 can expression of in the tumor a with A. J. S. C. of abscopal of intratumoral IL-12 Scholar Furthermore, IL-12 to the results in immune and to anti-PD-1 A. J. S. C. of abscopal of intratumoral IL-12 S. C. C. C. M. J. anti-PD-1 cancer immunotherapy T cell the and 2018; Scholar the of CXCR3 and associated in anti-PD-1 J.A. of the CXCR3 is for the of anti-PD-1 J. L. CXCL9 and are for immune responses immune checkpoint Cancer Res. Scholar is that a CXCL9 to via intratumoral IL-12 is for an anti-PD-1 often show expression of CXCR3 to T M. C. M. T.F. expression in melanoma associated with CD8+ Res. Scholar the of that or augment intratumoral expression of CXCR3 to not only and cytotoxic CD8+ T cells in the if to also promote in M. S. J. and J. J.A. C. S. tumor by a of Immunol. Scholar longitudinal biomarker data from with late-stage melanoma with intratumoral plasmid IL-12 or with electroporation identified associated with an therapy that a significant on-treatment increase of intratumoral CXCR3 A. S. S. M. M. L. M. A. of systemic immune responses in melanoma Scholar was that the intratumoral gradient to augment trafficking of CXCR3+ via result in a immune response. we identified and a tumor in the IL-12 response is CXCR3 of the tumor was that to an increase in CXCR3+ in the local of In CXCR3+ cells can tumor the of CXCR3 local therapy can the yielding systemic anti-tumor responses that can augment checkpoint that the axis is critical for IL-12 therapy and that of the axis via intratumoral expression of CXCL9 a addition to intratumoral cytokine in the response to intratumoral electroporation of plasmid IL-12 combination therapy with intratumoral CXCR3 including tumor and cells during a clinical in combination with to with melanoma to not to anti-PD-1 checkpoint based on a of tumor-infiltrating a of intratumoral cytotoxic CD8+ M. R. R. A. of IL-12 plasmid and blockade in Cancer Res. Scholar of from these that this combination could an on-treatment increase in the of CD8+ T cells in the of clinical response intratumoral expression of CXCR3 was only in responding to the combination therapy Furthermore, CXCR3 expression with and but not with T cell CXCR3 expression These with studies on anti-tumor M. C. M. T.F. expression in melanoma associated with CD8+ Res. M. S. J. and J. J.A. C. S. tumor by a of Immunol. Scholar the to CXCR3 and its associated could a critical in intratumoral IL-12 is for intratumoral electroporation therapy in a tumor was to the of CXCR3 in intratumoral anti-tumor responses. expression of CXCR3 is a that and A. A. Williams The CXCR3 is and is the cell by of Immunol. Scholar its by a of that can not only intratumoral CXCR3 expression but also a and of CXCR3+ CD8+ T cells in the local understand CXCR3+ T cells in response to a was to the of cells a CXCL9 was to the of the in tumors with or and the and the in the of the CXCL9 gradient from the with from the was by with an the and of from cells with for CXCL9 expression and for on CXCR3+ to was with the addition of an IL-12 response is on and the of CXCR3 expression on CD8+ T cells from the with or of cells with or CXCL9 was cells with tumor was with with or concomitant of and with and are data is a of with in with not the and with the blockade of in in of this anti-tumor of In a tumor C. A. A. of IL-12 intratumoral plasmid and 2018; Scholar significant in of tumor and CXCR3 is on various immune including cells and CD8+ T cells, we cell to this IL-12 response in the In the in a of tumor of CD8+ cells the in tumor a for CD8+ T cells in a systemic anti-tumor response Collectively, these data with clinical intratumoral CXCR3 expression with IL-12 combination therapy the of CXCR3+ in the the and the are critical to the anti-tumor of intratumoral and with electroporation tumor by the and the of T that CXCR3+ in the and the we that intratumoral expression of CXCL9 to efficient trafficking of into the tumor and ultimately of the tumors with a but of on by of on and of the tumors and was from the tumor The was the demonstrated of to as as and In treatment and T cell of and T cell activation. the also in the with this combination an increase of CD8+ T cells CXCL9 and IL-12 combination tumor by the to of treatment to tumor and immune response. with a but of by of of or and and for and expression in by with the of and of was to with the of T cells in treatment with with or on increase in the of CD8+ T cells with electroporation of IL-12 abscopal anti-tumor that intratumoral treatment with and in tumor with associated T cell we these immune could impact systemic tumor and tumor was to tumor and treatment a of intratumoral and with electroporation demonstrated of and on with only and In with and only treatment the with a of to this we and from a plasmid result in a anti-tumor We the expression and of from the plasmid was IL-12 expression from this was the expression from the plasmid and CXCL9 in and tumor for to and of the IL-12 and CXCL9 by an IL-12 cell and a and tumor we the plasmid to the in IL-12 expression with the treatment of and the electroporation of the plasmid in tumors in a abscopal response and with with IL-12 Furthermore, electroporation of the plasmid to in the of CXCR3+ CD8+ T cells and in the of CXCR3 expression These results that the tumoral CXCL9 gradient IL-12 anti-tumor CXCL9 and IL-12 combination therapy abscopal anti-tumor treatment for therapy to tumor a tumor with by of or and and a for and and of and of and are was the of the with that of by of the plasmid and treatment to tumor of tumor treatment with or The of plasmid was to the of from the plasmid by and tumors from the significant was in tumor the of the to that of electroporation of in a IL-12 anti-tumor was to the abscopal anti-tumor of in tumors to and intratumoral on and with or with with significant tumor in versus of the anti-tumor with versus tumor to electroporation of the of with versus electroporation of the of the with versus with the tumor these results that the addition of CXCL9 to an intratumoral IL-12 therapy anti-tumor including of and in electroporation of and in a significant tumor and in treatment to tumor on and with or plasmid of a for the treatment with tumor from electroporation of and anti-PD-1 studies have demonstrated a critical for CXCL9 in anti-PD-1 checkpoint J.A. of the CXCR3 is for the of anti-PD-1 J. L. CXCL9 and are for immune responses immune checkpoint Cancer Res. J. B. B. J. of CXCR3 in response to anti-PD-1 Scholar this a tumor was to this intratumoral in the of could anti-PD-1 anti-PD-1 checkpoint or an was with a intratumoral electroporation of with or anti-PD-1 therapy with or increase in in this tumor the addition of CXCL9 to the combination of IL-12 and checkpoint systemic for a significant in versus with IL-12 versus with Furthermore, in the with anti-PD-1 tumor or a response response as In the treatment with only or response of not responding to These results the clinical of checkpoint therapy with intratumoral electroporation of IL-12 and electroporation of and anti-PD-1 treatment for combination therapy to tumor on with or by of or on and a for of or a for and the of the anti-PD-1 with that of the of or treatment and response was by the in the biomarker data from a of intratumoral electroporation of plasmid IL-12 in with melanoma to not to anti-PD-1 checkpoint demonstrated a significant increase in transcripts associated with a and immune M. R. R. A. of IL-12 plasmid and blockade in Cancer Res. Scholar of this biomarker data that significant in CD8+ T cells in the clinical responses to intratumoral CXCR3 have that the of CXCR3 on was in to anti-PD-1 therapy with the clinical relevance of this axis the J. B. B. J. of CXCR3 in response to anti-PD-1 Scholar Furthermore, a significant increase of CXCL9 in the was in underscoring that a gradient is critical to its immune and clinical studies have J. J.A. C. S. tumor by a of Immunol. J. B. B. J. of CXCR3 in response to anti-PD-1 Scholar the of an intratumoral gradient in of cytotoxic CD8+ T cell into M. C. M. T.F. expression in melanoma associated with CD8+ Res. Scholar we that intratumoral with a augment this axis and a anti-PD-1 response the In this study, we for the functional relevance of the CXCR3 for IL-12 response and demonstrate that or this gradient in the tumor not only IL-12 but also checkpoint studies have demonstrated that intratumoral IL-12 treatment to the and of CD8+ T A. J. S. C. of abscopal of intratumoral IL-12 L. L. A. plasmid electroporation therapy in with melanoma systemic and intratumoral Immunol. Res. J. electroporation of IL-12 by CD8+ in a and of Immunol. 2012; Scholar understand immune for an anti-tumor cell and T cell studies In with J. electroporation of IL-12 by CD8+ in a and of Immunol. 2012; Scholar this response tumors to of CD8+ cells anti-tumor the of In the of or CD8+ cells in of tumor for this is that local IL-12 in the tumor intratumoral T cells to tumor as S. M. J. B. into tumor Scholar this localized is to the T response to the T cells and cells to critical for trafficking from the to of and CXCR3 in T cell Res. Scholar We that in the intratumoral IL-12 to the of in the of T cell Furthermore, by of a was to an abscopal to of CXCR3+ CD8+ T cells from the to the was blockade of The was and therapy and that this CXCR3 axis is in the response as T cells from the to the a with an of CXCR3 blockade a understanding of the of this axis was a of to the IL-12 response in tumors with blockade of tumors are to immunogenic and can to electroporation of this of tumor with blockade was to a immune by have to limit tumor by trafficking of cytotoxic CD8+ T cells into the L. R. J. intratumoral expression of CXCL9 the local of T cells immunotherapy with M. J. M. A. A. clinical response to 2017; Scholar IL-12 of A. J. S. C. of abscopal of intratumoral IL-12 Scholar we that in the tumor transcripts to not tumor C. M. M. C. R. expression and augment response to immunotherapy in Cancer Res. Scholar and as a of in Rev. Scholar limit the expression of to promote immune of these in these the with the as an to the of the are studies anti-tumor of as in the J. of of human melanoma J. Cancer. L. R. J.A. M. of in the tumor microenvironment for R. The CXCR3 in of CD8+ T but not of Scholar of that in with M. S. J. and J. J.A. C. S. tumor by a of Immunol. S. A. M. and cytokine Med. Scholar this on the impact of CXCL9 in combination with IL-12. CXCL9 not only the of CD8+ cytotoxic The of in the T cell and T Scholar but is also by cell a gradient and F. and functional Exp. Med. Scholar In cytotoxic and T The of in the T cell and T Scholar is by in R. L. tumor and Immunol. Scholar its the expression of of a to our data in C. plasmid CD8+ T cells and a CXCR3 in tumors that to Cancer Res. Scholar treatment of tumors with and reshape the immune to promote licensing of associated with and efficient and of CD8+ cytotoxic T cells in and In we significant in abscopal anti-tumor responses and combination treatment with IL-12 These data the of a CXCL9 gradient to a systemic immune response in tumors the can is that CXCL9 only to of trafficking of into these tumors and have to with in of T cell The expression of to with anti-tumor immune responses and in the of CXCL9 M. C. J. F. and T cell and immune in Scholar and demonstrated expression of with not in tumor IL-12 drives expression via an intratumoral CXCL9 result in a durable anti-tumor studies have an of gradient in the demonstrated that the axis was for T cell J.A. of the CXCR3 is for the of anti-PD-1 Scholar The the of the axis in T cells dendritic cells for in is that a in our electroporation to secretion of the in the in of T cells in the tumor to studies have the of this axis in anti-PD-1 responses. we have demonstrated that intratumoral IL-12 therapy can with anti-PD-1 checkpoint to the in licensing of and systemic A. J. S. C. of abscopal of intratumoral IL-12 S. C. C. C. M. J. anti-PD-1 cancer immunotherapy T cell the and 2018; M. R. R. A. of IL-12 plasmid and blockade in Cancer Res. C. plasmid CD8+ T cells and a CXCR3 in tumors that to Cancer Res. Scholar demonstrated that the of response to in this or responding tumor S. J. M. M. C. C. of a to blockade by CD8+ T Scholar with a of and a of T cell and activation. These that anti-PD-1 treatment in a benefit from of the with an of CD8+ T cells. we show that intratumoral electroporation of anti-PD-1 response in was anti-PD-1 therapy and treatment in this was an benefit of CXCL9 and IL-12 in this We that this therapy to the of but is also that this was to a of IL-12 to the in combination with of of this combination can the axis and as in C. B. J. therapy with and in cancer Cancer Res. 2017; Scholar studies have that the of anti-PD-1 blockade was of CXCL9 but not a of CXCL9 in anti-PD-1 J.A. of the CXCR3 is for the of anti-PD-1 Scholar this on of IL-12 and direct of CXCL9 on tumor J. J. J. A. functional of the in Biol. Scholar studies are to anti-tumor our results that the CXCR3/CXCL9 axis is critical for IL-12 therapy and that and of this axis via intratumoral expression of CXCL9 to a immune response with anti-tumor Furthermore, intratumoral electroporation of plasmid IL-12 with plasmid CXCL9 the anti-PD-1 with combination clinical studies provides a for this to the and tumor cell of in with and and in with with and in with and with and in in the with cells in a of abscopal anti-tumor responses in the was also with cells. was by was the a is and is with tumors from to and to and into treatment of the tumors or the tumor in with by the and IL-12 plasmid C. A. A. of IL-12 intratumoral plasmid and 2018; Scholar is a plasmid that for and by a and driven by a The CXCL9 plasmid was from a from for CXCL9 with and and a The was with and into plasmid plasmid the a was from the with and was with and and the into was with and The plasmid is a plasmid driven by a and for and with a in the was from the of in a was with and the and with and and and from or and in electroporation and with for treatment for the The treatment tumors with of or on by of or on and The tumors with of or on and plasmid to the in was into by electroporation a for C. A. A. of IL-12 intratumoral plasmid and 2018; Scholar that with with as CXCR3 on and and and cells cells in with and cells cell was with and cells a of was with of for was to with of plasmid for to the cell and for to cell and to and with a with and tumor cells as and in and with and to a or with for for with by and on for The for the and with was an was in or from clinical to and into as S. R. A. of plasmid via electroporation to of and tumors in cell Cancer Res. Scholar in and in for by the and on a and data was by from by cell with and with and with in and with for cells and to in for the from and with and with CXCR3 cells with for to cells and in with of and with the of CXCL9 was on of the of the cell was for and cells in the with and with for with in a of of and on a on cells or on a versus and expression from and in in the was and was with expression was and the expression of for of was with and and for The from and on an and transcripts on the The was for clinical tumor and on the of treatment in and in from these and was to the on a and was with of transcripts and data are to the of functional cell IL-12 cells to human or to the of IL-12 by the and The was as by the a of IL-12 from to IL-12 cells with of IL-12 for and of the to of was for and with a clinical a that response to anti-PD-1 based on the of CD8+ that are M. R. R. A. of IL-12 plasmid and blockade in Cancer Res. Scholar this to not to anti-PD-1 in this if of CD8+ or as by S. J. R. C. A. C. treatment with intratumoral electroporation of 2017; Scholar for human and by an and driven by a was into a of a of in the was with a of and a of was as a of on the of was on and of treatment on by clinical as by data are as and to treatment was for IntroductionThe overall tumor immune contexture characterized by the location, density, and functional organization of immune cells in the tumor microenvironment is widely recognized as an important determinant of clinical outcome.1Fridman W.H. Pagès F. Sautès-Fridman C. Galon J. The immune contexture in human tumours: impact on clinical outcome.Nat. Rev. Cancer. 2012; 12: 298-306https://doi.org/10.1038/nrc3245Google Scholar T cell inflamed tumors are often characterized by transcriptional profiles associated with T cell markers, pro-inflammatory cytokines, and chemokines. These profiles often correspond with clinical benefit to various immunotherapies, including checkpoint blockade and vaccines.2Gajewski T.F. Corrales L. Williams J. Horton B. Sivan A. Spranger S. Cancer immunotherapy targets based on understanding the T cell-inflamed versus non-T cell-inflamed tumor microenvironment.Adv. Exp. Med. Biol. 2017; 1036: 19-31https://doi.org/10.1007/978-3-319-67577-0_2Google Scholar,3Trujillo J.A. Sweis R.F. Bao R. Luke J.J. T cell–inflamed versus non-T cell–inflamed tumors: a conceptual framework for cancer immunotherapy drug development and combination therapy selection.Cancer Immunol. Res. 2018; 6: 990-1000https://doi.org/10.1158/2326-6066.cir-18-0277Google Scholar Several immune cells (MDSCs, TAMs, TANs, Tregs, suppressive B cells), endothelial cells, and stromal cells can infiltrate the tumor during its progression. These cells act to limit T cell function and trafficking via direct contact or secretion of suppressive molecules, rendering a poorly immunogenic tumor microenvironment (TME).4Kim R. Emi M. Tanabe of during Res. L. cells in tumor and therapy 12: M. associated in and S. C. cells that and are by Immunol. 2018; R. T cells and the suppressive tumor Immunol. A. J.A. A. B cell in cancer and anti-tumor Immunol. 2017; L. S. J. of the immune response by Immunol. 2018; Scholar that can this from a suppressive T to a T cell-inflamed are in and clinical cell trafficking is a the of and on T cells, to from the the expression of as These and from the in for and that are in the or are to the and to and to the microenvironment of of and and of an Immunol. Scholar Several studies have the of for T cell into the tumors and for associated anti-tumor A. A. B. The and of in tumor Immunol. 2012; in the cancer microenvironment and relevance in cancer Rev. Immunol. 2017; Scholar the of the axis is often a critical checkpoint that can a J. J.J. T.F. for CXCR3 during trafficking 6: and clinical studies have the of to the to promote anti-tumor J. J.J. T.F. for CXCR3 during trafficking 6: S. S. C. CXCR3 tumor by in a cancer J. J. M. of CXCR3 on tumor-infiltrating associated with in J. Exp. J. expression by CD8+ T cells is associated with in melanoma with Res. of CXCR3 on cells and CXCR3 in with cell in response to systemic Scholar Furthermore, have to important in efficient in and of T cells, including T cells by with J.A. of the CXCR3 is for the of anti-PD-1 J. L. CXCL9 and are for immune responses immune checkpoint Cancer Res. M. S. R. and T Scholar The axis and of immune cells. CXCR3 is on immune cell including T cells, CD8+ T cells, and S. The of CXCR3 and its in and Med. 2018; studies that interferon-gamma is a critical for intratumoral T cell via of its L. R. J. intratumoral expression of CXCL9 the local of T cells immunotherapy with Scholar and the of clinical response to anti-PD-1 including M. J. M. A. A. clinical response to 2017; Scholar We and have in clinical and that intratumoral expression of pro-inflammatory as IL-12 can expression of in the tumor a with A. J. S. C. of abscopal of intratumoral IL-12 Scholar Furthermore, IL-12 to the results in immune and to anti-PD-1 A. J. S. C. of abscopal of intratumoral IL-12 S. C. C. C. M. J. anti-PD-1 cancer immunotherapy T cell the and 2018; Scholar the of CXCR3 and associated in anti-PD-1 J.A. of the CXCR3 is for the of anti-PD-1 J. L. CXCL9 and are for immune responses immune checkpoint Cancer Res. Scholar is that a CXCL9 to via intratumoral IL-12 is for an anti-PD-1 often show expression of CXCR3 to T M. C. M. T.F. expression in melanoma associated with CD8+ Res. Scholar the of that or augment intratumoral expression of CXCR3 to not only and cytotoxic CD8+ T cells in the if to also promote in M. S. J. and J. J.A. C. S. tumor by a of Immunol. Scholar longitudinal biomarker data from with late-stage melanoma with intratumoral plasmid IL-12 or with electroporation identified associated with an therapy that a significant on-treatment increase of intratumoral CXCR3 A. S. S. M. M. L. M. A. of systemic immune responses in melanoma Scholar was that the intratumoral gradient to augment trafficking of CXCR3+ via result in a immune response. we identified and a tumor in the IL-12 response is CXCR3 of the tumor was that to an increase in CXCR3+ in the local of In CXCR3+ cells can tumor the of CXCR3 local therapy can the yielding systemic anti-tumor responses that can augment checkpoint that the axis is critical for IL-12 therapy and that of the axis via intratumoral expression of CXCL9 a addition to intratumoral cytokine in the

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