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Immune profiling and therapies in cancer by Obaid.pptx

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Dr Amal Mariyadas Boobily
Dr Amal Mariyadas Boobily

Immune profiling and therapies in cancer by Obaid.pptx

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Immune profiling and therapies in cancer PRESENTED BY DR OBAIDULLA (JR2) GEN SX GMC ORAI
INTRODUCTION Unlike traditional cytotoxic chemotherapy , immunotherapy targets and unleashes the immune system of the pt to generate an antitumor response. Various types of immune therapies such as cancer vaccines and immune checkpoint inhibitors (ICPIs) approved for clinical use have shown remarkable results in various cancers how ever it is also recognized that many pts do not respond to these therapies. Auto immune toxicity / immune related adverse events, and occasionally fatal too.
Why immune profiling? Against these unwanted immune therapy results , efforts have been made to profile the TME (tumor micro environment ) for biomarker identification and discovery of novel treatment strategies to improve treatment outcomes.
Types of Immune Cell Profiling Transcriptomic based ; 1. Microarrays 2. Bulk RNA Sequencing 3. conventional IHC 4. Fluorescence based flow cytometry Proteomic based ; 1. single cell assay for transposase accessible chromatin sequencing (sc-ATAC-seq) 2. single cell RNA sequencing 3. Multiplexed IHC 4. Cytometry by time of flight
Clinical applications of immune cell profiling ICP provides a powerful tool to conduct deep immunophenotyping at the single cell level. Studies have revealed a complex network of immune cell in the TME in various cancers such as HCC, Ca Breast, and CR carcinomas; thus, each tumor has been identified to carry its own specific immune signature, which can affect the prognosis independent of its TNM staging. Several studies have attempted to discover biomarkers in cancers such as melanomas, (yet to be validated and conducted in large prospective studies).
Immunoscore assay Exception of ICP Validated as a prognostic risk factor in several cancers ( CR Ca, breast and lung cancers) and has some predictive value in CR Ca. A scoring system to summarize the density of CD3+ and CD8+ T-cells within the tumor and its invasive margin. Higher infiltration of immune cells in the tumor correlates with a better prognosis. In a study of colon cancer , the assay was found to be reproducible and robust, and in a multivariable analysis, its prognostic power was found to be independent of pts age, T-stage, N-stage, microsatellite instability, and existing prognostic factors. A lower score is s/o poor over all survival for all cancers.
In a study of CR cancer a high immunoscore predicted benefit of 6 months of FOLFOX regime over 3 months, whereas a low score did not significantly benefit from 6 months of FOLFOX .
CANCER IMMUNOTHERAPY Real breakthrough in cancer immunotherapy came in 21st century after the discovery of T cell immune checkpoints such as CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed cell death protein 1) These checkpoints prevents autoimmune reactions by playing a negative regulatory role to prevent excessive T cell activation, but cancer cells can escape immune clearance by suppressing these immune checkpoints. Discovery of the PD-1/L-1 axis coupled with the development of breakthrough immune checkpoint inhibitor therapies in cancers resulted in the 2018 Nobel prize in medicine
Checkpoint inhibitor immunotherapy . PD-1 on T CELL and PD-L1 on tumor cell and tumor infiltrating immune cells, including APCs, B & T-cells. . Both PD-1 and PD-L1 are therapeutic targets and for this several monoclonal ABs have been developed. . Anti PD-1 Abs- NIVOLUMAB & PEMBROLIZUMAB and the Anti PD-L1 ABs DURVALUMAB, ATEZOLIZUMAB and AVELUMAB. . CTLA-4, another identified target for therapeutic blockade ( eg; IPILIMUMAB & TREMELIMUMAB )
Immune profiling and therapies in cancer by Obaid.pptx
Predictive biomarkers for checkpoint inhibitors PD1/L1 remains the most widely used and validated biomarkers for immunotherapies. PD-L1 is heterogeneously expressed and a dynamic biomarker- the threshold b/w a +ve (positive correlation b/w PD-L1 positive tumors and clinical efficacy of PD-1 pathway blocker) and a ve report can depend on the type of antibody being used and the type of tissue being studied. Although PD-L1 is an IMPERFECT biomarker too (highly expression does not guarantee tumor response to checkpoint therapy). Commercial PD-L1 IHC assays are currently in clinical use such as 22C3, 28-8 & SP-263; shown high concordance and interchangeability in an international harmonizing project.
dMMR- deficient mismatch repair; another validated biomarker to checkpoint inhibitor therapy, tumors lacking this is hypermutated.
Checkpoint inhibitor toxicity Unique spectrum of side effects k/a irAEs (immune related adverse events) that includes dermatological, GI related, hepatic & endocrine, fatigue being the m/c, More common with combination therapy like CTLA-4 + PD-1 as compared to monotherapy. Mx; withhold the drug, C/S therapy, additional immunosuppression in severe/refractory cases.
CART Therapy Chimeric antigen receptor (CAR) T-cell therapy / next generation cellular therapy ; a form of genetically modified autologous immunotherapy that uses the individuals own T cell and transduces them with a gene that encodes a CAR to direct the pts T cell against the leukemic cell. Example 1 ; CD 19, a B-cell marker, highly expressed in B cell malignancies, >80% result in relapsed B cell leukemias, cells persists > 1 yr Example 2; BCMA (B cell maturation antigen), a plasma cell marker, CARs targeting these have given 80- 100% result in refractory multiple myeloma
Side effects of CAR T- cell therapy 1. CRS (cytokine release syndrome); seen in nearly all treated pts, fever, flue, hypotension, hypoxia, MODS (rare) tocilizumab- an IL-6 monoclonal AB, is Rx for CRS >grd2, 2. ICANS (immune effector cell associated neurotoxicity syndrome) ; ch/b- confusion, somnolence, aphasia, it si d/t trafficking of CARs in CNS. Rx is Corticosteroid.
CANCER VACCINE SIPULEUCEL- T; a therapeutic vaccine, prepared from peripheral blood mononuclear cells with a unique fusion with GM-CSF (granulocyte macrophage colony stimulating factor) and PAP (prostatic acid phosphatase), termed as PA2024. Each dose contains min of 50 million autologous CD54+ cells activated with PAP&/gm-csf. Over all median survival in phase 3 of RCT was clinically meaningful with 4.1 months
Oncolytic viruses TALIMOGENE LAHERPAREPVEC (T-VEC) ; genetically modified herpes virus, given intralesionally. Produces direct oncolytic effect from the viral infection and lytic replication and induction of a systemic immune response Mostly for unresectable tumors, injectable cutaneous, s/c, nodal melanomas with limited visceral disease. Increase in over all response rate > 25% as compared with GM-CSF.
CONCLUSION IMMUNOTHERAPY has revolutionized cancer treatment in 21st century. ICPIs have now become a standard of care across several solid and lymphoid malignancies based on large phase 3 RCTs that have demonstrated superior OS and response rate. PD-L1 most validated and accepted biomarker till date. IC profiling with newer proteomic technologies will open the gateway to better designed and personalized in the near future. CAR T- CELL therapies have proved its effectiveness in relapsed/refractory B-cell malignancies & MM.
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Immune profiling and therapies in cancer by Obaid.pptx

  • 1. Immune profiling and therapies in cancer PRESENTED BY DR OBAIDULLA (JR2) GEN SX GMC ORAI
  • 2. INTRODUCTION Unlike traditional cytotoxic chemotherapy , immunotherapy targets and unleashes the immune system of the pt to generate an antitumor response. Various types of immune therapies such as cancer vaccines and immune checkpoint inhibitors (ICPIs) approved for clinical use have shown remarkable results in various cancers how ever it is also recognized that many pts do not respond to these therapies. Auto immune toxicity / immune related adverse events, and occasionally fatal too.
  • 3. Why immune profiling? Against these unwanted immune therapy results , efforts have been made to profile the TME (tumor micro environment ) for biomarker identification and discovery of novel treatment strategies to improve treatment outcomes.
  • 4. Types of Immune Cell Profiling Transcriptomic based ; 1. Microarrays 2. Bulk RNA Sequencing 3. conventional IHC 4. Fluorescence based flow cytometry Proteomic based ; 1. single cell assay for transposase accessible chromatin sequencing (sc-ATAC-seq) 2. single cell RNA sequencing 3. Multiplexed IHC 4. Cytometry by time of flight
  • 5. Clinical applications of immune cell profiling ICP provides a powerful tool to conduct deep immunophenotyping at the single cell level. Studies have revealed a complex network of immune cell in the TME in various cancers such as HCC, Ca Breast, and CR carcinomas; thus, each tumor has been identified to carry its own specific immune signature, which can affect the prognosis independent of its TNM staging. Several studies have attempted to discover biomarkers in cancers such as melanomas, (yet to be validated and conducted in large prospective studies).
  • 6. Immunoscore assay Exception of ICP Validated as a prognostic risk factor in several cancers ( CR Ca, breast and lung cancers) and has some predictive value in CR Ca. A scoring system to summarize the density of CD3+ and CD8+ T-cells within the tumor and its invasive margin. Higher infiltration of immune cells in the tumor correlates with a better prognosis. In a study of colon cancer , the assay was found to be reproducible and robust, and in a multivariable analysis, its prognostic power was found to be independent of pts age, T-stage, N-stage, microsatellite instability, and existing prognostic factors. A lower score is s/o poor over all survival for all cancers.
  • 7. In a study of CR cancer a high immunoscore predicted benefit of 6 months of FOLFOX regime over 3 months, whereas a low score did not significantly benefit from 6 months of FOLFOX .
  • 8. CANCER IMMUNOTHERAPY Real breakthrough in cancer immunotherapy came in 21st century after the discovery of T cell immune checkpoints such as CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed cell death protein 1) These checkpoints prevents autoimmune reactions by playing a negative regulatory role to prevent excessive T cell activation, but cancer cells can escape immune clearance by suppressing these immune checkpoints. Discovery of the PD-1/L-1 axis coupled with the development of breakthrough immune checkpoint inhibitor therapies in cancers resulted in the 2018 Nobel prize in medicine
  • 9. Checkpoint inhibitor immunotherapy . PD-1 on T CELL and PD-L1 on tumor cell and tumor infiltrating immune cells, including APCs, B & T-cells. . Both PD-1 and PD-L1 are therapeutic targets and for this several monoclonal ABs have been developed. . Anti PD-1 Abs- NIVOLUMAB & PEMBROLIZUMAB and the Anti PD-L1 ABs DURVALUMAB, ATEZOLIZUMAB and AVELUMAB. . CTLA-4, another identified target for therapeutic blockade ( eg; IPILIMUMAB & TREMELIMUMAB )
  • 11. Predictive biomarkers for checkpoint inhibitors PD1/L1 remains the most widely used and validated biomarkers for immunotherapies. PD-L1 is heterogeneously expressed and a dynamic biomarker- the threshold b/w a +ve (positive correlation b/w PD-L1 positive tumors and clinical efficacy of PD-1 pathway blocker) and a ve report can depend on the type of antibody being used and the type of tissue being studied. Although PD-L1 is an IMPERFECT biomarker too (highly expression does not guarantee tumor response to checkpoint therapy). Commercial PD-L1 IHC assays are currently in clinical use such as 22C3, 28-8 & SP-263; shown high concordance and interchangeability in an international harmonizing project.
  • 12. dMMR- deficient mismatch repair; another validated biomarker to checkpoint inhibitor therapy, tumors lacking this is hypermutated.
  • 13. Checkpoint inhibitor toxicity Unique spectrum of side effects k/a irAEs (immune related adverse events) that includes dermatological, GI related, hepatic & endocrine, fatigue being the m/c, More common with combination therapy like CTLA-4 + PD-1 as compared to monotherapy. Mx; withhold the drug, C/S therapy, additional immunosuppression in severe/refractory cases.
  • 14. CART Therapy Chimeric antigen receptor (CAR) T-cell therapy / next generation cellular therapy ; a form of genetically modified autologous immunotherapy that uses the individuals own T cell and transduces them with a gene that encodes a CAR to direct the pts T cell against the leukemic cell. Example 1 ; CD 19, a B-cell marker, highly expressed in B cell malignancies, >80% result in relapsed B cell leukemias, cells persists > 1 yr Example 2; BCMA (B cell maturation antigen), a plasma cell marker, CARs targeting these have given 80- 100% result in refractory multiple myeloma
  • 15. Side effects of CAR T- cell therapy 1. CRS (cytokine release syndrome); seen in nearly all treated pts, fever, flue, hypotension, hypoxia, MODS (rare) tocilizumab- an IL-6 monoclonal AB, is Rx for CRS >grd2, 2. ICANS (immune effector cell associated neurotoxicity syndrome) ; ch/b- confusion, somnolence, aphasia, it si d/t trafficking of CARs in CNS. Rx is Corticosteroid.
  • 16. CANCER VACCINE SIPULEUCEL- T; a therapeutic vaccine, prepared from peripheral blood mononuclear cells with a unique fusion with GM-CSF (granulocyte macrophage colony stimulating factor) and PAP (prostatic acid phosphatase), termed as PA2024. Each dose contains min of 50 million autologous CD54+ cells activated with PAP&/gm-csf. Over all median survival in phase 3 of RCT was clinically meaningful with 4.1 months
  • 17. Oncolytic viruses TALIMOGENE LAHERPAREPVEC (T-VEC) ; genetically modified herpes virus, given intralesionally. Produces direct oncolytic effect from the viral infection and lytic replication and induction of a systemic immune response Mostly for unresectable tumors, injectable cutaneous, s/c, nodal melanomas with limited visceral disease. Increase in over all response rate > 25% as compared with GM-CSF.
  • 18. CONCLUSION IMMUNOTHERAPY has revolutionized cancer treatment in 21st century. ICPIs have now become a standard of care across several solid and lymphoid malignancies based on large phase 3 RCTs that have demonstrated superior OS and response rate. PD-L1 most validated and accepted biomarker till date. IC profiling with newer proteomic technologies will open the gateway to better designed and personalized in the near future. CAR T- CELL therapies have proved its effectiveness in relapsed/refractory B-cell malignancies & MM.
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