Studies of oncolytic viruses to date have primarily used increase in tumor-infiltrating lymphocytes (TILs) as a readout of immune activation, commonly referred to as \u201cconverting cold tumors into hot\u201d. However, while this biomarker may be informative with other immunotherapies such as immune checkpoint blockade, in the context of oncolytic virus therapy such readouts are highly non-specific. It is unknown whether the increase in TILs with OV therapy represents predominantly tumor-reactive, OV-reactive, or bystander T cells. Second, while a strong anti-OV response T cell response is likely generated with OV therapy, it is unknown whether these OV-reactive T cells positively or negatively impact anti-tumor immunity. Lastly, it is unknown how different aspects of oncolytic virus biology, including replication capacity, expression of therapeutic transgenes, and combination therapies impact the balance between the antiviral and anti-tumor immunity. We are actively pursuing these questions in the lab.<\/p>\n<\/div>\n<\/div>\n<\/div>\n
[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/Figure-3.jpg” title_text=”Figure 3.” _builder_version=”4.9.0″ _module_preset=”default” width=”90%” module_alignment=”center” custom_padding=”2px|||||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” width=”96.1%” module_alignment=”center” min_height=”10.6px” custom_margin=”-35px||-5px|||” custom_padding=”18px|0px|1px|9px||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure 3. <\/b>Intratumoral<\/b> oncolytic virus therapy normalizes the TCR repertoire across the tumor sites. <\/b>Top: Overall repertoire breadth and distribution of shared TCR clones across the treated and distant tumors. Bottom: unbiased identification of virus- vs. tumor-reactive TCRs demonstrates their dominance, phenotypic states, and distribution across the treated and distant tumors.<\/h6>\n
[\/et_pb_text][\/et_pb_column][\/et_pb_row][et_pb_row column_structure=”1_2,1_2″ make_equal=”on” _builder_version=”4.9.0″ module_alignment=”center” min_height=”742.9px” custom_margin=”30px|auto|60px|auto|false|” custom_padding=”20px|0px|20px|0px|true|” saved_tabs=”all” locked=”off” collapsed=”off”][et_pb_column type=”1_2″ _builder_version=”3.25″ background_color_gradient_direction=”35deg” custom_padding=”40px|40px|40px|40px” custom_padding__hover=”|||”][et_pb_text _builder_version=”4.9.0″ header_font=”||||||||” header_3_font=”Playfair Display|700|||||||” header_3_text_color=”#2b2b2b” header_3_font_size=”28px” header_3_line_height=”1.5em” width=”100%” module_alignment=”left” custom_margin=”-4px||-20px|||”]<\/p>\n
Potentiation of T cell-based immunotherapies by oncolytic viruses<\/strong><\/h2>\n<\/h1>\n
[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/Picture1-2.jpg” title_text=”Diagram of adoptive T cell therapies, immunomodulatory antibodies, and chemotherapy and targeted therapies.” _builder_version=”4.9.0″ _module_preset=”default” width=”50%” module_alignment=”center” custom_margin=”||1px|||” custom_padding=”17px|||||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ text_font=”||||||||” text_text_color=”#141414″ text_line_height=”1.9em” header_font=”||||||||” header_2_font=”||||||||” module_alignment=”center” min_height=”338.4px” custom_margin=”||-100px|||” custom_padding=”29px||2px|||”]<\/p>\n
\n\n\nSeveral features of oncolytic virus therapy generate a strong rationale for their combinations with other agents. For example, modification of the tumor microenvironment by the viruses improves sensitivity of the tumor to cytotoxic agents such as chemotherapy and targeted agents. Priming of tumor-specific immune responses generates a pool of T cells the efficacy of which is further potentiated by systemic immunomodulatory antibodies such as immune checkpoint inhibitors. Finally, by modification of the tumor microenvironment and improved priming, oncolytic viruses can increase the efficacy of adoptive T cell therapy. These features, combined with potential for engineered oncolytic viruses create opportunities for studies of biology and therapeutic efficacy of different combinations.<\/p>\n<\/div>\n<\/div>\n<\/div>\n
<\/div>\n[\/et_pb_text][\/et_pb_column][et_pb_column type=”1_2″ _builder_version=”3.25″ background_color_gradient_direction=”35deg” custom_padding=”40px|40px|40px|40px” custom_padding__hover=”|||”][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-4-1.jpg” title_text=”Figure 4″ force_fullwidth=”on” _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”||-1px|||” custom_padding=”6px|||||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” width=”100%” custom_margin=”|-89px|1px|||” custom_padding=”|0px||||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure 4. NDV increases tumor lymphocyte infiltration and promotes response to systemic immune checkpoint blockade (ICB). <\/b>A. Treatment schema (B16 model). B. Numbers of intratumoral CD8+, CD4+FoxP3- and CD4+FoxP3+ T cells in distant tumors calculated from flow cytometry. C. Survival with NDV+anti-PD-1 or anti-PD-L1 combinations.<\/h6>\n
[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-5.jpg” title_text=”Figure 5. NDV induces tumor infiltration with tumor-specific adoptively-transferred T cells. Left: Treatment schema utilizing intratumoral NDV in combination with systemic ACT of luciferase-expressing transgenic T cells targeting B16 Trp1 antigen. Animals were implanted with bilateral flank B16 tumors; only right tumor was injected with NDV. Right: Infiltration of Trp1 lymphocytes into the NDV-treated and distant tumors. ” _builder_version=”4.9.0″ _module_preset=”default” width=”100%” custom_margin=”2px||1px|||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”||-32px|||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure 5.<\/b> NDV induces tumor infiltration with tumor-specific adoptively-transferred T cells. <\/b>Left: Treatment schema utilizing intratumoral NDV in combination with systemic ACT of luciferase-expressing transgenic T cells targeting B16 Trp1 antigen. Animals were implanted with bilateral flank B16 tumors; only right tumor was injected with NDV. Right: Infiltration of Trp1 lymphocytes into the NDV-treated and distant tumors.<\/h6>\n
[\/et_pb_text][\/et_pb_column][\/et_pb_row][et_pb_row make_equal=”on” _builder_version=”4.9.0″ module_alignment=”center” min_height=”878.5px” custom_margin=”60px|auto|60px|auto|true|” custom_padding=”0px|0px|1px|0px||” saved_tabs=”all” locked=”off” collapsed=”off”][et_pb_column type=”4_4″ _builder_version=”3.25″ background_color_gradient_direction=”35deg” custom_padding=”40px|40px|40px|40px” custom_padding__hover=”|||”][et_pb_text _builder_version=”4.9.0″ header_font=”||||||||” header_3_font=”Playfair Display|700|||||||” header_3_text_color=”#2b2b2b” header_3_font_size=”28px” header_3_line_height=”1.5em” width=”100%” custom_margin=”||10px|”]<\/p>\n
Engineering novel oncolytic viruses as cancer immunotherapeutics<\/b><\/h2>\n
[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-6.jpg” title_text=”Figure 6. Oncolytic viruses can be engineered to deliver therapeutic payloads to tumors.” align=”center” _builder_version=”4.9.0″ _module_preset=”default” width=”45%” custom_margin=”||3px|||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”||40px|||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure <\/b>6<\/b>.<\/b> Oncolytic viruses can be engineered to deliver therapeutic payloads to tumors.<\/b><\/h6>\n
[\/et_pb_text][et_pb_text _builder_version=”4.9.0″ text_font=”||||||||” text_text_color=”#141414″ text_line_height=”1.9em” header_font=”||||||||” header_2_font=”||||||||” module_alignment=”center” min_height=”189.4px” custom_margin=”||7px|||” custom_padding=”||0px|||”]<\/p>\n
\n\n\nIn addition to directly activating the innate and adaptive immune response, oncolytic viruses can be used as delivery vehicles for therapeutic transgenes directly into the tumor. Depending on the application, such transgenes can range from strategies to boost the innate or adaptive immune cells (e.g. through expression of cytokines) to expression of tumor antigens to stimulate tumor-specific immunity in a vaccine-like fashion. We have generated a number of engineered NDVs expressing different immunostimulatory transgenes and demonstrated that this can significantly improve the therapeutic potential of these agents.<\/p>\n<\/div>\n<\/div>\n<\/div>\n
<\/div>\n[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-7-1.jpg” title_text=”Figure 7. Engineering strategies can improve therapeutic efficacy of oncolytic virus. Left: intratumoral therapy with wild-type NDV identifies inducible costimulator (ICOS) as one of the highest upregulated genes in tumor. Right: therapeutic effect of NDV encoding ICOS ligand (ICOSL) in bilateral flank melanoma mouse models. ” align=”center” _builder_version=”4.9.0″ _module_preset=”default” width=”85%” custom_padding=”29px|||||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” width=”100%” module_alignment=”center” custom_margin=”-47px|-27px|-3px|||” custom_padding=”22px|0px|1px|0px||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure 7.<\/b> Engineering strategies can improve therapeutic efficacy of oncolytic virus. <\/b>Left: intratumoral therapy with wild-type NDV identifies inducible costimulator (ICOS) as one of the highest upregulated genes in tumor. Right: therapeutic effect of NDV encoding ICOS ligand (ICOSL) in bilateral flank melanoma mouse models.<\/h6>\n
[\/et_pb_text][\/et_pb_column][\/et_pb_row][et_pb_row column_structure=”2_5,3_5″ make_equal=”on” _builder_version=”4.9.0″ module_alignment=”center” min_height=”1206.7px” custom_margin=”|auto|59px|auto||” custom_padding=”0px|0px|0px|0px|true|” saved_tabs=”all” locked=”off” collapsed=”off”][et_pb_column type=”2_5″ _builder_version=”3.25″ background_color_gradient_direction=”35deg” custom_padding=”40px|40px|40px|40px” custom_padding__hover=”|||”][et_pb_text _builder_version=”4.9.0″ header_font=”||||||||” header_3_font=”Playfair Display|700|||||||” header_3_text_color=”#2b2b2b” header_3_font_size=”28px” header_3_line_height=”1.5em” width=”100%” custom_margin=”||10px|”]<\/p>\n
Mechanisms of response and resistance to immunotherapy in gynecologic cancers<\/b><\/h2>\n
[\/et_pb_text][et_pb_text _builder_version=”4.9.0″ text_font=”||||||||” text_text_color=”#141414″ text_line_height=”1.9em” header_font=”||||||||” header_2_font=”||||||||” module_alignment=”center” min_height=”338.4px” custom_margin=”3px||7px|||” custom_padding=”||1px|||”]<\/p>\n
Our direct connection to patients and clinical trials provides us with the unique opportunity to study the biospecimens to understand how therapeutic interventions impact the immune response in humans. These studies range across a number of interventions, including standard and investigational and take advantage of tumor and blood genomic, tumor microenvironment, and TCR repertoire parameters that enable us to identify the mechanisms of response and resistance to immunotherapy in patients and to potentially develop novel biomarkers. For example, using tumor samples collected from multiple sites from newly-diagnosed ovarian cancer patients, we identified a substantial degree of inter-tumor heterogeneity both on the level of number and functional states of immune cells. Identifying strategies to address this heterogeneity will be key to successful immunotherapy in these patients. In another recent study, we demonstrated that in patients with mismatch repair-deficient endometrial cancers, several tumor microenvironment parameters such as presence of dysfunctional T cells and their interaction with PD-L1-expressing cells could strongly predict therapeutic efficacy.<\/div>\n<\/div>\n[\/et_pb_text][\/et_pb_column][et_pb_column type=”3_5″ _builder_version=”3.25″ background_color_gradient_direction=”35deg” custom_padding=”40px|40px|40px|40px” custom_padding__hover=”|||”][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-8-1.jpg” title_text=”Figure 8. Ovarian tumors from the same patients exhibit substantial inter-tumor immune heterogeneity. Left: multiplex IF images of several tumor sites isolated from the same patient. Right: multi-site single-cell RNA seq analysis demonstrating differences in predominant T cell phenotypes across the sites. ” _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”59px||1px|||” custom_padding=”0px|||||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”||-30px|||” custom_padding=”||0px|||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure 8. Ovarian tumors from the same patients exhibit substantial inter-tumor immune heterogeneity.<\/strong> Left: multiplex IF images of several tumor sites isolated from the same patient. Right: multi-site single-cell RNA seq analysis demonstrating differences in predominant T cell phenotypes across the sites.<\/h6>\n[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-9-1.jpg” title_text=”Figure 9. Tumor microenvironment parameters predict therapeutic response in dMMR endometrial cancer. ” _builder_version=”4.9.0″ _module_preset=”default” custom_padding=”50px|||||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”-48px||1px|||” custom_padding=”23px|||||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure <\/b>9<\/b>. Tumor microenvironment parameters predict therapeutic response in <\/b>dMMR<\/b> endometrial cancer. <\/b><\/h6>\n
[\/et_pb_text][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”8px|||||” custom_padding=”||1px|||”]<\/p>\n
Several ongoing projects include:<\/p>\n
\n- Evolution of immune response to intraperitoneal oncolytic virus therapy in patients with advanced ovarian and colorectal cancers<\/li>\n
- Understanding of response to differential sequencing of immunotherapy and chemoradiation in locally advanced cervical cancer<\/li>\n
- Predictors of response to immune checkpoint blockade in patients with endometrial and ovarian cancers<\/li>\n<\/ul>\n
[\/et_pb_text][\/et_pb_column][\/et_pb_row][et_pb_row make_equal=”on” _builder_version=”4.9.0″ module_alignment=”center” min_height=”1158.5px” custom_margin=”48px|auto|48px|auto|true|” custom_padding=”0px|0px|3px|0px||” saved_tabs=”all” locked=”off” collapsed=”off”][et_pb_column type=”4_4″ _builder_version=”3.25″ background_color_gradient_direction=”35deg” custom_padding=”40px|40px|40px|40px” custom_padding__hover=”|||”][et_pb_text _builder_version=”4.9.0″ header_font=”||||||||” header_3_font=”Playfair Display|700|||||||” header_3_text_color=”#2b2b2b” header_3_font_size=”28px” header_3_line_height=”1.5em” width=”100%” custom_margin=”||10px|”]<\/p>\n
Understanding tumor cell-intrinsic mechanisms that drive immune recognition or resistance<\/b><\/h2>\n
[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-10.jpg” title_text=”Figure 10. Various tumor cell-intrinsic mechanisms ultimately control their recognition by the immune system” align=”center” _builder_version=”4.9.0″ _module_preset=”default” module_alignment=”center” custom_margin=”61px|166px||||” custom_padding=”0px|||163px||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” width=”100%” custom_margin=”-47px||40px|||” custom_padding=”20px|0px||||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure 10. Various tumor cell-intrinsic mechanisms ultimately control their recognition by the immune system<\/b><\/h6>\n
[\/et_pb_text][et_pb_text _builder_version=”4.9.0″ text_font=”||||||||” text_text_color=”#141414″ text_line_height=”1.9em” header_font=”||||||||” header_2_font=”||||||||” module_alignment=”center” min_height=”280.4px” custom_margin=”||7px|||” custom_padding=”||0px|||”]<\/p>\n
\n\n\nThere is a growing appreciation that tumor genomic features shape the phenotypes of the tumor microenvironment, including the recruitment, infiltration, and functional states of T cells as well as responsiveness to immunotherapy. Such features include genomic alterations that lead to generation of immunogenic neoantigens that promote immune recognition (e.g. tumor mutation burden), but also alterations in antigen presentation machinery (e.g. HLA loss) that inhibit the immune response. Tumor genomic alterations in addition drive activation of tumor cell-intrinsic signaling pathways that can promote (e.g. type I IFN) or inhibit (e.g. beta-catenin) immune response. Understanding how cancer genetics defines tumor cell-intrinsic immune signaling as well as recognition by the innate and adaptive immune cells is critically important for the design of effective immunotherapeutic interventions. By using genetically-engineered syngeneic tumor models and organoids, we are evaluating how specific genetic alterations relevant to human cancers drive immune recognition.<\/p>\n<\/div>\n<\/div>\n<\/div>\n
<\/div>\n[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-11-1.jpg” title_text=”Figure 11. Establishment of isogenic endometrial cancer murine organoids. Left panels: Representative images of PIK3CAE545K and PIK3CAE545Kp53R172Horganoids. Right panel: Expression of TdTomato by the PTEN-\/- organoids after Cre mRNA transfection.” align=”center” _builder_version=”4.9.0″ _module_preset=”default” width=”60%” custom_margin=”-32px||0px|||” custom_padding=”28px|||||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” width=”100%” custom_margin=”|-10px|-41px|-1px||” custom_padding=”|2px|0px|0px||”]<\/p>\n
Figure 11. Establishment of isogenic endometrial cancer murine organoids.<\/b> Left panels:<\/b> Representative images of two\u00a0organoids. Right panel:<\/b> Expression of TdTomato by the PTEN-\/- organoids after Cre mRNA transfection.<\/h6>\n
[\/et_pb_text][\/et_pb_column][\/et_pb_row][\/et_pb_section][et_pb_section fb_built=”1″ disabled_on=”off|off|off” admin_label=”Footer Fullwidth – Section 13″ module_class=”footer-section” _builder_version=”4.9.0″ background_color=”#c7eafb” background_image=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2022\/10\/Rectangle-3.png” max_width=”100%” max_width_tablet=”” max_width_phone=”” max_width_last_edited=”on|phone” module_alignment=”center” custom_margin=”86px|||176px|false|false” custom_padding=”3px|0px|0px|0px|false|false” animation_style=”slide” animation_direction=”bottom” animation_intensity_slide=”14%” animation_starting_opacity=”100%” global_module=”3741″ saved_tabs=”all” locked=”off” collapsed=”on”][et_pb_row _builder_version=”4.9.0″ background_color=”RGBA(0,0,0,0)” background_color_gradient_direction=”38deg” module_alignment=”center” custom_margin=”|auto||147px||” custom_padding=”1px|||||” locked=”off” collapsed=”off”][et_pb_column type=”4_4″ _builder_version=”3.25″ custom_padding=”|||” custom_padding__hover=”|||”][et_pb_social_media_follow _builder_version=”4.9.0″ _module_preset=”default” background_color=”RGBA(0,0,0,0)” text_orientation=”center”][et_pb_social_media_follow_network social_network=”twitter” url=”https:\/\/twitter.com\/DmitriyZamarin” use_icon_font_size=”on” icon_font_size=”24px” _builder_version=”4.9.0″ _module_preset=”default” background_color=”RGBA(0,0,0,0)” background_enable_color=”on” follow_button=”off” url_new_window=”on”]twitter[\/et_pb_social_media_follow_network][\/et_pb_social_media_follow][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” text_text_color=”#FFFFFF” text_font_size=”24px”]<\/p>\n
Contact Us<\/strong><\/p>\n[\/et_pb_text][\/et_pb_column][\/et_pb_row][et_pb_row column_structure=”1_3,1_3,1_3″ _builder_version=”4.9.0″ background_color=”RGBA(0,0,0,0)” background_color_gradient_direction=”38deg” module_alignment=”center” custom_margin=”|auto|-2px|auto||” custom_padding=”0px||0px|||” locked=”off” collapsed=”off”][et_pb_column type=”1_3″ _builder_version=”4.9.0″ custom_padding=”|||” custom_padding__hover=”|||”][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” text_font=”||||||||” text_text_color=”#FFFFFF” text_line_height=”22px”]<\/p>\n
<\/p>\n
Several features of oncolytic virus therapy generate a strong rationale for their combinations with other agents. For example, modification of the tumor microenvironment by the viruses improves sensitivity of the tumor to cytotoxic agents such as chemotherapy and targeted agents. Priming of tumor-specific immune responses generates a pool of T cells the efficacy of which is further potentiated by systemic immunomodulatory antibodies such as immune checkpoint inhibitors. Finally, by modification of the tumor microenvironment and improved priming, oncolytic viruses can increase the efficacy of adoptive T cell therapy. These features, combined with potential for engineered oncolytic viruses create opportunities for studies of biology and therapeutic efficacy of different combinations.<\/p>\n<\/div>\n<\/div>\n<\/div>\n
[\/et_pb_text][\/et_pb_column][et_pb_column type=”1_2″ _builder_version=”3.25″ background_color_gradient_direction=”35deg” custom_padding=”40px|40px|40px|40px” custom_padding__hover=”|||”][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-4-1.jpg” title_text=”Figure 4″ force_fullwidth=”on” _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”||-1px|||” custom_padding=”6px|||||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” width=”100%” custom_margin=”|-89px|1px|||” custom_padding=”|0px||||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure 4. NDV increases tumor lymphocyte infiltration and promotes response to systemic immune checkpoint blockade (ICB). <\/b>A. Treatment schema (B16 model). B. Numbers of intratumoral CD8+, CD4+FoxP3- and CD4+FoxP3+ T cells in distant tumors calculated from flow cytometry. C. Survival with NDV+anti-PD-1 or anti-PD-L1 combinations.<\/h6>\n
[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-5.jpg” title_text=”Figure 5. NDV induces tumor infiltration with tumor-specific adoptively-transferred T cells. Left: Treatment schema utilizing intratumoral NDV in combination with systemic ACT of luciferase-expressing transgenic T cells targeting B16 Trp1 antigen. Animals were implanted with bilateral flank B16 tumors; only right tumor was injected with NDV. Right: Infiltration of Trp1 lymphocytes into the NDV-treated and distant tumors. ” _builder_version=”4.9.0″ _module_preset=”default” width=”100%” custom_margin=”2px||1px|||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”||-32px|||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure 5.<\/b> NDV induces tumor infiltration with tumor-specific adoptively-transferred T cells. <\/b>Left: Treatment schema utilizing intratumoral NDV in combination with systemic ACT of luciferase-expressing transgenic T cells targeting B16 Trp1 antigen. Animals were implanted with bilateral flank B16 tumors; only right tumor was injected with NDV. Right: Infiltration of Trp1 lymphocytes into the NDV-treated and distant tumors.<\/h6>\n
[\/et_pb_text][\/et_pb_column][\/et_pb_row][et_pb_row make_equal=”on” _builder_version=”4.9.0″ module_alignment=”center” min_height=”878.5px” custom_margin=”60px|auto|60px|auto|true|” custom_padding=”0px|0px|1px|0px||” saved_tabs=”all” locked=”off” collapsed=”off”][et_pb_column type=”4_4″ _builder_version=”3.25″ background_color_gradient_direction=”35deg” custom_padding=”40px|40px|40px|40px” custom_padding__hover=”|||”][et_pb_text _builder_version=”4.9.0″ header_font=”||||||||” header_3_font=”Playfair Display|700|||||||” header_3_text_color=”#2b2b2b” header_3_font_size=”28px” header_3_line_height=”1.5em” width=”100%” custom_margin=”||10px|”]<\/p>\n
Engineering novel oncolytic viruses as cancer immunotherapeutics<\/b><\/h2>\n
[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-6.jpg” title_text=”Figure 6. Oncolytic viruses can be engineered to deliver therapeutic payloads to tumors.” align=”center” _builder_version=”4.9.0″ _module_preset=”default” width=”45%” custom_margin=”||3px|||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”||40px|||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure <\/b>6<\/b>.<\/b> Oncolytic viruses can be engineered to deliver therapeutic payloads to tumors.<\/b><\/h6>\n
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In addition to directly activating the innate and adaptive immune response, oncolytic viruses can be used as delivery vehicles for therapeutic transgenes directly into the tumor. Depending on the application, such transgenes can range from strategies to boost the innate or adaptive immune cells (e.g. through expression of cytokines) to expression of tumor antigens to stimulate tumor-specific immunity in a vaccine-like fashion. We have generated a number of engineered NDVs expressing different immunostimulatory transgenes and demonstrated that this can significantly improve the therapeutic potential of these agents.<\/p>\n<\/div>\n<\/div>\n<\/div>\n
[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-7-1.jpg” title_text=”Figure 7. Engineering strategies can improve therapeutic efficacy of oncolytic virus. Left: intratumoral therapy with wild-type NDV identifies inducible costimulator (ICOS) as one of the highest upregulated genes in tumor. Right: therapeutic effect of NDV encoding ICOS ligand (ICOSL) in bilateral flank melanoma mouse models. ” align=”center” _builder_version=”4.9.0″ _module_preset=”default” width=”85%” custom_padding=”29px|||||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” width=”100%” module_alignment=”center” custom_margin=”-47px|-27px|-3px|||” custom_padding=”22px|0px|1px|0px||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure 7.<\/b> Engineering strategies can improve therapeutic efficacy of oncolytic virus. <\/b>Left: intratumoral therapy with wild-type NDV identifies inducible costimulator (ICOS) as one of the highest upregulated genes in tumor. Right: therapeutic effect of NDV encoding ICOS ligand (ICOSL) in bilateral flank melanoma mouse models.<\/h6>\n
[\/et_pb_text][\/et_pb_column][\/et_pb_row][et_pb_row column_structure=”2_5,3_5″ make_equal=”on” _builder_version=”4.9.0″ module_alignment=”center” min_height=”1206.7px” custom_margin=”|auto|59px|auto||” custom_padding=”0px|0px|0px|0px|true|” saved_tabs=”all” locked=”off” collapsed=”off”][et_pb_column type=”2_5″ _builder_version=”3.25″ background_color_gradient_direction=”35deg” custom_padding=”40px|40px|40px|40px” custom_padding__hover=”|||”][et_pb_text _builder_version=”4.9.0″ header_font=”||||||||” header_3_font=”Playfair Display|700|||||||” header_3_text_color=”#2b2b2b” header_3_font_size=”28px” header_3_line_height=”1.5em” width=”100%” custom_margin=”||10px|”]<\/p>\n
Mechanisms of response and resistance to immunotherapy in gynecologic cancers<\/b><\/h2>\n
[\/et_pb_text][et_pb_text _builder_version=”4.9.0″ text_font=”||||||||” text_text_color=”#141414″ text_line_height=”1.9em” header_font=”||||||||” header_2_font=”||||||||” module_alignment=”center” min_height=”338.4px” custom_margin=”3px||7px|||” custom_padding=”||1px|||”]<\/p>\n
[\/et_pb_text][\/et_pb_column][et_pb_column type=”3_5″ _builder_version=”3.25″ background_color_gradient_direction=”35deg” custom_padding=”40px|40px|40px|40px” custom_padding__hover=”|||”][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-8-1.jpg” title_text=”Figure 8. Ovarian tumors from the same patients exhibit substantial inter-tumor immune heterogeneity. Left: multiplex IF images of several tumor sites isolated from the same patient. Right: multi-site single-cell RNA seq analysis demonstrating differences in predominant T cell phenotypes across the sites. ” _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”59px||1px|||” custom_padding=”0px|||||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”||-30px|||” custom_padding=”||0px|||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure 8. Ovarian tumors from the same patients exhibit substantial inter-tumor immune heterogeneity.<\/strong> Left: multiplex IF images of several tumor sites isolated from the same patient. Right: multi-site single-cell RNA seq analysis demonstrating differences in predominant T cell phenotypes across the sites.<\/h6>\n[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-9-1.jpg” title_text=”Figure 9. Tumor microenvironment parameters predict therapeutic response in dMMR endometrial cancer. ” _builder_version=”4.9.0″ _module_preset=”default” custom_padding=”50px|||||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”-48px||1px|||” custom_padding=”23px|||||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure <\/b>9<\/b>. Tumor microenvironment parameters predict therapeutic response in <\/b>dMMR<\/b> endometrial cancer. <\/b><\/h6>\n
[\/et_pb_text][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” custom_margin=”8px|||||” custom_padding=”||1px|||”]<\/p>\n
Several ongoing projects include:<\/p>\n
\n- Evolution of immune response to intraperitoneal oncolytic virus therapy in patients with advanced ovarian and colorectal cancers<\/li>\n
- Understanding of response to differential sequencing of immunotherapy and chemoradiation in locally advanced cervical cancer<\/li>\n
- Predictors of response to immune checkpoint blockade in patients with endometrial and ovarian cancers<\/li>\n<\/ul>\n
[\/et_pb_text][\/et_pb_column][\/et_pb_row][et_pb_row make_equal=”on” _builder_version=”4.9.0″ module_alignment=”center” min_height=”1158.5px” custom_margin=”48px|auto|48px|auto|true|” custom_padding=”0px|0px|3px|0px||” saved_tabs=”all” locked=”off” collapsed=”off”][et_pb_column type=”4_4″ _builder_version=”3.25″ background_color_gradient_direction=”35deg” custom_padding=”40px|40px|40px|40px” custom_padding__hover=”|||”][et_pb_text _builder_version=”4.9.0″ header_font=”||||||||” header_3_font=”Playfair Display|700|||||||” header_3_text_color=”#2b2b2b” header_3_font_size=”28px” header_3_line_height=”1.5em” width=”100%” custom_margin=”||10px|”]<\/p>\n
Understanding tumor cell-intrinsic mechanisms that drive immune recognition or resistance<\/b><\/h2>\n
[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-10.jpg” title_text=”Figure 10. Various tumor cell-intrinsic mechanisms ultimately control their recognition by the immune system” align=”center” _builder_version=”4.9.0″ _module_preset=”default” module_alignment=”center” custom_margin=”61px|166px||||” custom_padding=”0px|||163px||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” width=”100%” custom_margin=”-47px||40px|||” custom_padding=”20px|0px||||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure 10. Various tumor cell-intrinsic mechanisms ultimately control their recognition by the immune system<\/b><\/h6>\n
[\/et_pb_text][et_pb_text _builder_version=”4.9.0″ text_font=”||||||||” text_text_color=”#141414″ text_line_height=”1.9em” header_font=”||||||||” header_2_font=”||||||||” module_alignment=”center” min_height=”280.4px” custom_margin=”||7px|||” custom_padding=”||0px|||”]<\/p>\n
\n\n\nThere is a growing appreciation that tumor genomic features shape the phenotypes of the tumor microenvironment, including the recruitment, infiltration, and functional states of T cells as well as responsiveness to immunotherapy. Such features include genomic alterations that lead to generation of immunogenic neoantigens that promote immune recognition (e.g. tumor mutation burden), but also alterations in antigen presentation machinery (e.g. HLA loss) that inhibit the immune response. Tumor genomic alterations in addition drive activation of tumor cell-intrinsic signaling pathways that can promote (e.g. type I IFN) or inhibit (e.g. beta-catenin) immune response. Understanding how cancer genetics defines tumor cell-intrinsic immune signaling as well as recognition by the innate and adaptive immune cells is critically important for the design of effective immunotherapeutic interventions. By using genetically-engineered syngeneic tumor models and organoids, we are evaluating how specific genetic alterations relevant to human cancers drive immune recognition.<\/p>\n<\/div>\n<\/div>\n<\/div>\n
<\/div>\n[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-11-1.jpg” title_text=”Figure 11. Establishment of isogenic endometrial cancer murine organoids. Left panels: Representative images of PIK3CAE545K and PIK3CAE545Kp53R172Horganoids. Right panel: Expression of TdTomato by the PTEN-\/- organoids after Cre mRNA transfection.” align=”center” _builder_version=”4.9.0″ _module_preset=”default” width=”60%” custom_margin=”-32px||0px|||” custom_padding=”28px|||||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” width=”100%” custom_margin=”|-10px|-41px|-1px||” custom_padding=”|2px|0px|0px||”]<\/p>\n
Figure 11. Establishment of isogenic endometrial cancer murine organoids.<\/b> Left panels:<\/b> Representative images of two\u00a0organoids. Right panel:<\/b> Expression of TdTomato by the PTEN-\/- organoids after Cre mRNA transfection.<\/h6>\n
[\/et_pb_text][\/et_pb_column][\/et_pb_row][\/et_pb_section][et_pb_section fb_built=”1″ disabled_on=”off|off|off” admin_label=”Footer Fullwidth – Section 13″ module_class=”footer-section” _builder_version=”4.9.0″ background_color=”#c7eafb” background_image=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2022\/10\/Rectangle-3.png” max_width=”100%” max_width_tablet=”” max_width_phone=”” max_width_last_edited=”on|phone” module_alignment=”center” custom_margin=”86px|||176px|false|false” custom_padding=”3px|0px|0px|0px|false|false” animation_style=”slide” animation_direction=”bottom” animation_intensity_slide=”14%” animation_starting_opacity=”100%” global_module=”3741″ saved_tabs=”all” locked=”off” collapsed=”on”][et_pb_row _builder_version=”4.9.0″ background_color=”RGBA(0,0,0,0)” background_color_gradient_direction=”38deg” module_alignment=”center” custom_margin=”|auto||147px||” custom_padding=”1px|||||” locked=”off” collapsed=”off”][et_pb_column type=”4_4″ _builder_version=”3.25″ custom_padding=”|||” custom_padding__hover=”|||”][et_pb_social_media_follow _builder_version=”4.9.0″ _module_preset=”default” background_color=”RGBA(0,0,0,0)” text_orientation=”center”][et_pb_social_media_follow_network social_network=”twitter” url=”https:\/\/twitter.com\/DmitriyZamarin” use_icon_font_size=”on” icon_font_size=”24px” _builder_version=”4.9.0″ _module_preset=”default” background_color=”RGBA(0,0,0,0)” background_enable_color=”on” follow_button=”off” url_new_window=”on”]twitter[\/et_pb_social_media_follow_network][\/et_pb_social_media_follow][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” text_text_color=”#FFFFFF” text_font_size=”24px”]<\/p>\n
Contact Us<\/strong><\/p>\n[\/et_pb_text][\/et_pb_column][\/et_pb_row][et_pb_row column_structure=”1_3,1_3,1_3″ _builder_version=”4.9.0″ background_color=”RGBA(0,0,0,0)” background_color_gradient_direction=”38deg” module_alignment=”center” custom_margin=”|auto|-2px|auto||” custom_padding=”0px||0px|||” locked=”off” collapsed=”off”][et_pb_column type=”1_3″ _builder_version=”4.9.0″ custom_padding=”|||” custom_padding__hover=”|||”][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” text_font=”||||||||” text_text_color=”#FFFFFF” text_line_height=”22px”]<\/p>\n
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[\/et_pb_text][\/et_pb_column][\/et_pb_row][et_pb_row make_equal=”on” _builder_version=”4.9.0″ module_alignment=”center” min_height=”1158.5px” custom_margin=”48px|auto|48px|auto|true|” custom_padding=”0px|0px|3px|0px||” saved_tabs=”all” locked=”off” collapsed=”off”][et_pb_column type=”4_4″ _builder_version=”3.25″ background_color_gradient_direction=”35deg” custom_padding=”40px|40px|40px|40px” custom_padding__hover=”|||”][et_pb_text _builder_version=”4.9.0″ header_font=”||||||||” header_3_font=”Playfair Display|700|||||||” header_3_text_color=”#2b2b2b” header_3_font_size=”28px” header_3_line_height=”1.5em” width=”100%” custom_margin=”||10px|”]<\/p>\n
Understanding tumor cell-intrinsic mechanisms that drive immune recognition or resistance<\/b><\/h2>\n
[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-10.jpg” title_text=”Figure 10. Various tumor cell-intrinsic mechanisms ultimately control their recognition by the immune system” align=”center” _builder_version=”4.9.0″ _module_preset=”default” module_alignment=”center” custom_margin=”61px|166px||||” custom_padding=”0px|||163px||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” width=”100%” custom_margin=”-47px||40px|||” custom_padding=”20px|0px||||” hover_enabled=”0″ sticky_enabled=”0″]<\/p>\n
Figure 10. Various tumor cell-intrinsic mechanisms ultimately control their recognition by the immune system<\/b><\/h6>\n
[\/et_pb_text][et_pb_text _builder_version=”4.9.0″ text_font=”||||||||” text_text_color=”#141414″ text_line_height=”1.9em” header_font=”||||||||” header_2_font=”||||||||” module_alignment=”center” min_height=”280.4px” custom_margin=”||7px|||” custom_padding=”||0px|||”]<\/p>\n
There is a growing appreciation that tumor genomic features shape the phenotypes of the tumor microenvironment, including the recruitment, infiltration, and functional states of T cells as well as responsiveness to immunotherapy. Such features include genomic alterations that lead to generation of immunogenic neoantigens that promote immune recognition (e.g. tumor mutation burden), but also alterations in antigen presentation machinery (e.g. HLA loss) that inhibit the immune response. Tumor genomic alterations in addition drive activation of tumor cell-intrinsic signaling pathways that can promote (e.g. type I IFN) or inhibit (e.g. beta-catenin) immune response. Understanding how cancer genetics defines tumor cell-intrinsic immune signaling as well as recognition by the innate and adaptive immune cells is critically important for the design of effective immunotherapeutic interventions. By using genetically-engineered syngeneic tumor models and organoids, we are evaluating how specific genetic alterations relevant to human cancers drive immune recognition.<\/p>\n<\/div>\n<\/div>\n<\/div>\n
[\/et_pb_text][et_pb_image src=”https:\/\/labs.icahn.mssm.edu\/zamarinlab\/wp-content\/uploads\/sites\/510\/2023\/11\/fig-11-1.jpg” title_text=”Figure 11. Establishment of isogenic endometrial cancer murine organoids. Left panels: Representative images of PIK3CAE545K and PIK3CAE545Kp53R172Horganoids. Right panel: Expression of TdTomato by the PTEN-\/- organoids after Cre mRNA transfection.” align=”center” _builder_version=”4.9.0″ _module_preset=”default” width=”60%” custom_margin=”-32px||0px|||” custom_padding=”28px|||||”][\/et_pb_image][et_pb_text _builder_version=”4.9.0″ _module_preset=”default” width=”100%” custom_margin=”|-10px|-41px|-1px||” custom_padding=”|2px|0px|0px||”]<\/p>\n
Figure 11. Establishment of isogenic endometrial cancer murine organoids.<\/b> Left panels:<\/b> Representative images of two\u00a0organoids. Right panel:<\/b> Expression of TdTomato by the PTEN-\/- organoids after Cre mRNA transfection.<\/h6>\n
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