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cancer immunotherapy

A detailed ppt about cancer immunotherapy.
includes:-
Immunosurveillance and Immunoediting
Dentritic cell vaccines
Antibody therapy
Combined therapy
immune blockades
Cytokine therapy
T cell therapy

Include latest research finding about therapy.

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cancer immunotherapy

  1. 1. Cancer ImmunotherapyCancer Immunotherapy Arun.V. 3rd semeste, MSc. Biochemistry and Molecular Biology 14368005
  2. 2. Immunosurveillance and Immunoediting The greatest trouble with the idea of immunosurveillance is that it can’t be shown to exist in experimental animals (Thomas, 1982) There is little ground for optimism about cancer (Burnet, 1957) The greatest trouble with the idea of immunosurveillance is that it can’t be shown to exist in experimental animals (Thomas, 1982) Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  3. 3. Immunosurveillance and Immunoediting • In 1909, Paul Ehrlich proposed that the incidence of cancer would be much greater were it not for the vigilance of our immune defense system in identifying and eliminating nascent tumor cells. • About 50 years later, two scientists, Lewis Thomas and Frank MacFarlane Burnet, took Paul Ehrlich’s original idea a step further and proposed that T cell was the pivotal sentinel in the immune system’s response against cancer. • This elaboration led to the coinage of the term “immune surveillance or immunosurveillance” to describe the concept whereby the immune system is on perpetual alert against transformed cells • In 1909, Paul Ehrlich proposed that the incidence of cancer would be much greater were it not for the vigilance of our immune defense system in identifying and eliminating nascent tumor cells. • About 50 years later, two scientists, Lewis Thomas and Frank MacFarlane Burnet, took Paul Ehrlich’s original idea a step further and proposed that T cell was the pivotal sentinel in the immune system’s response against cancer. • This elaboration led to the coinage of the term “immune surveillance or immunosurveillance” to describe the concept whereby the immune system is on perpetual alert against transformed cells Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  4. 4. Immunosurveillance and Immunoediting • Osías Stutman showed in the 1970s that mice supposedly lacking an intact immune system (so-called nude mice) did not become more susceptible to tumor growth as predicted by the theory. • Thus, the theory of immunosurveillance remained controversial • until an important scientific article entitled this paper was published in Nature on April 26, 2001. • this paper unambiguously showed that the immune system can and often does prevent tumors from developing, and thus plays a strong protective role against cancer. • These researchers also uncovered important new insights regarding the immune system and tumor development that they coined immunoediting Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  5. 5. • Utilizing nude mouse, the authors showed that lymphocytes and IFN- gamma, cooperate to inhibit the development of both spontaneous and carcinogen-induced tumors. • Immune system imperfect, and some tumor cells escape identification and go on to cause cancer. • Such tumors are imposed with selection pressure by immune system only those which manage to escape this pressure cause cancer • same way as bacteria can become resistant to antibiotic treatment and lead to more potent and harmful strains • researchers demonstrate that there are ways to over come the “camouflage” of such escaped tumors by increasing their antigen expression and making them visible to the immune system. • This suggests that even tumors that have escaped recognition can be turned into targets for an immune response. • This has yet to be implemented in the field of therapy Immunosurveillance and Immunoediting • Utilizing nude mouse, the authors showed that lymphocytes and IFN- gamma, cooperate to inhibit the development of both spontaneous and carcinogen-induced tumors. • Immune system imperfect, and some tumor cells escape identification and go on to cause cancer. • Such tumors are imposed with selection pressure by immune system only those which manage to escape this pressure cause cancer • same way as bacteria can become resistant to antibiotic treatment and lead to more potent and harmful strains • researchers demonstrate that there are ways to over come the “camouflage” of such escaped tumors by increasing their antigen expression and making them visible to the immune system. • This suggests that even tumors that have escaped recognition can be turned into targets for an immune response. • This has yet to be implemented in the field of therapy Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  6. 6. Immunosurveillance and Immunoediting
  7. 7. • connection between cancer and the immune system was first uncovered nearly 100 years ago • In the early 1890s, Dr. William B. Coley, a NY physician he observed dramatic disappearance of malignant tumors that he observed in cancer patients who had contracted acute streptococcal infections. • he injected live streptococci into a patient with inoperable cancer to see whether the patient’s tumor would regress. • After trying 3 different bacterial cultures to the patient, he finally injected a fourth that resulted in the complete disappearance of the tumor. • Dr. Coley continued to pursue his approach and ultimately developed a mixture of killed bacteria that became known as Coley’s mixed bacterial toxin • He and other physicians treated over 1,000 cancer patients with this substance, with varied success • bacterial products of which it was composed had acted as immune potentiators. they had stimulated certain immune cells to kill the cancer • Today, cancer immunology is a rapidly advancing field and Dr. Coley has come to be regarded as the “father of cancer immunotherapy.” Coley’s mixed bacterial toxin • connection between cancer and the immune system was first uncovered nearly 100 years ago • In the early 1890s, Dr. William B. Coley, a NY physician he observed dramatic disappearance of malignant tumors that he observed in cancer patients who had contracted acute streptococcal infections. • he injected live streptococci into a patient with inoperable cancer to see whether the patient’s tumor would regress. • After trying 3 different bacterial cultures to the patient, he finally injected a fourth that resulted in the complete disappearance of the tumor. • Dr. Coley continued to pursue his approach and ultimately developed a mixture of killed bacteria that became known as Coley’s mixed bacterial toxin • He and other physicians treated over 1,000 cancer patients with this substance, with varied success • bacterial products of which it was composed had acted as immune potentiators. they had stimulated certain immune cells to kill the cancer • Today, cancer immunology is a rapidly advancing field and Dr. Coley has come to be regarded as the “father of cancer immunotherapy.” Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  8. 8. • Dentritic Cell Vaccines • Antibody Therapy • Cytokine Therapy • Adoptive T cell Therapy • Immune checkpoint blockade • Combined Therapy Types of Immunotherapy • Dentritic Cell Vaccines • Antibody Therapy • Cytokine Therapy • Adoptive T cell Therapy • Immune checkpoint blockade • Combined Therapy Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  9. 9. Dentritic Cell Vaccines Dentritic cells express high levels of class I and class II MHC and co- stimulatory molecules - unique ability to activate naive T cells Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  10. 10. • CD8+ cytotoxic T lymphocytes (CTLs), are the principle effectors of anti-tumor immunity • CTLs become sensitized to Ag by encountering peptide-class I MHC on the surface of professional APCs • But this is not sufficient to activate the effector response. CD4+ T helper cells must also be present to recognize peptides displayed on the class II MHC molecules of the APCs • this results in secretion of Cytokines by TH cellsthat - expansion and maturation of CTLs • Coexpression of co-stimulatory molecules, such as CD80/B7.1 and CD86/B7.2, by the APCs is also required to deliver a second confirmatory signal to the T cells via the CD28 molecule expressed on their surface • No co-stimulatory signals - T-cell anergy and is a mechanism for maintaining peripheral tolerance to self antigens Why Dentritic Cell ? • CD8+ cytotoxic T lymphocytes (CTLs), are the principle effectors of anti-tumor immunity • CTLs become sensitized to Ag by encountering peptide-class I MHC on the surface of professional APCs • But this is not sufficient to activate the effector response. CD4+ T helper cells must also be present to recognize peptides displayed on the class II MHC molecules of the APCs • this results in secretion of Cytokines by TH cellsthat - expansion and maturation of CTLs • Coexpression of co-stimulatory molecules, such as CD80/B7.1 and CD86/B7.2, by the APCs is also required to deliver a second confirmatory signal to the T cells via the CD28 molecule expressed on their surface • No co-stimulatory signals - T-cell anergy and is a mechanism for maintaining peripheral tolerance to self antigens Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  11. 11. TumorAg’recognizedbyTcellsTumorAg’recognizedbyTcells Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  12. 12. • DC are activated in the presence of tumor antigens, which may be a single tumor-specific peptide/protein or a tumor cell lysate (a solution of broken down tumor cells). • activated dendritic cells are put back into the body where they provoke an immune response to the cancer cells. • Adjuvants are sometimes used • More modern dendritic cell therapies include the use of antibodies that bind to receptors on the surface of dendritic cells. Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. • clinical response takes time to build up but remissions can be very long-lasting Dentritic Cell Vaccines Targeting antigen to DCs Ex vivo • DC are activated in the presence of tumor antigens, which may be a single tumor-specific peptide/protein or a tumor cell lysate (a solution of broken down tumor cells). • activated dendritic cells are put back into the body where they provoke an immune response to the cancer cells. • Adjuvants are sometimes used • More modern dendritic cell therapies include the use of antibodies that bind to receptors on the surface of dendritic cells. Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. • clinical response takes time to build up but remissions can be very long-lasting Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  13. 13. Sipuleucel-T Ex Vivo • treatment of metastatic prostate cancer with sipuleucel-T (also known as APC 8015), which is a cellular product based on enriched blood APCs that are briefly cultured with a fusion protein of prostatic acid phosphatase (PAP) and GM-CSF • an approximately 4-month-prolonged median survival in Phase III trials. • Sipuleucel-T has been approved by the US Food and Drug Administration (FDA)Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  14. 14. Sipuleucel -T Mechanism of action Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  15. 15. • rilimogene alvacirepvec a.k.a rilimogene glafolivec • by Bavarian Nordic for the treatment of metastatic castration- resistant prostate cancer (mCRPC). • Passed Phase 3, waiting for FDA approval PROSTVAC Ex Vivo • rilimogene alvacirepvec a.k.a rilimogene glafolivec • by Bavarian Nordic for the treatment of metastatic castration- resistant prostate cancer (mCRPC). • Passed Phase 3, waiting for FDA approval •designed to enable immune system to recognize & attack PC cells by triggering a specific & targeted T cell immune response to cancer cells that express the tumor-associated antigen prostate-specific antigen (PSA). Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  16. 16. • administered subcutaneously • trigger immune response by using virus-based immunotherapies that carry the tumor-associated antigen PSA (prostate-specific antigen) along with 3 natural human immune-enhancing costimulatory molecules collectively designated as TRICOM (LFA-3, ICAM-1, and B7.1). • Adjuvant low-dose granulocyte-macrophage colony- stimulating factor (GM-CSF, 100 µg) PROSTVAC Ex Vivo • administered subcutaneously • trigger immune response by using virus-based immunotherapies that carry the tumor-associated antigen PSA (prostate-specific antigen) along with 3 natural human immune-enhancing costimulatory molecules collectively designated as TRICOM (LFA-3, ICAM-1, and B7.1). • Adjuvant low-dose granulocyte-macrophage colony- stimulating factor (GM-CSF, 100 µg) regimen consists of an initial PSA-TRICOM vaccinia-based priming dose, followed by 6 subsequent PSA-TRICOM fowlpox-based boosting doses. These 7 subcutaneous injections are given within a 5-month treatment period. Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  17. 17. PROSTVAC Mode of Action Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  18. 18. Vaccines under clinical trial Ex Vivo Cancer immunotherapy via dendritic cells Karolina P and Jacques B NATURE REVIEWS | CANCER VOLUME 12 | APRIL 2012 Cancer immunotherapy via dendritic cells Karolina P and Jacques B NATURE REVIEWS | CANCER VOLUME 12 | APRIL 2012
  19. 19. • using chimeric proteins that are comprised of an Ab that is specific for a DC receptor fused to a selected antigen • Ralph Steinman and colleagues demonstrated that the specific targeting of antigens to DCs in vivo elicits potent antigen-specific CD4+ and CD8+ T cell-mediated immunity • They activated two subsets of DCs : CD8+ DCs & CD8– DCs Dentritic Cell Vaccines Targeting antigen to DCs in vivo • using chimeric proteins that are comprised of an Ab that is specific for a DC receptor fused to a selected antigen • Ralph Steinman and colleagues demonstrated that the specific targeting of antigens to DCs in vivo elicits potent antigen-specific CD4+ and CD8+ T cell-mediated immunity • They activated two subsets of DCs : CD8+ DCs & CD8– DCs Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  20. 20. Dentritic Cell Vaccines Targeting antigen to DCs in vivo CD8– DCsCD8+ DCs CD205 A marker antigen recognized by mAb 33D1 CD205 A marker antigen recognized by mAb 33D1 MHC I MHC II ActivatesTH1 cell IL-12-independent mechanism ActivatesTH1 cell IL-12-dependent classical mechanism Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  21. 21. Clinical response to dendritic cell vaccination in a patient with non- Hodgkin.s lymphoma. Prevaccine CT scan images demonstrate (a) periaortic lymph nodes and (c) a paracardial mass. (b) and (d) demonstrate complete resolution of tumors 10 months following vaccination with dendritic cells. Clinical response to dendritic cell vaccination in a patient with non- Hodgkin.s lymphoma. Prevaccine CT scan images demonstrate (a) periaortic lymph nodes and (c) a paracardial mass. (b) and (d) demonstrate complete resolution of tumors 10 months following vaccination with dendritic cells. Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  22. 22. Ab therapy for cancer has become established over the past 15 years & is now one of the most successful & important strategies for treating patients with haematological malignancies & solid tumours Ab therapy for cancer has become established over the past 15 years & is now one of the most successful & important strategies for treating patients with haematological malignancies & solid tumours The Magic BulletsCirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  23. 23. • Ab therapy targets cancer antigents or Neoantigents • Ideally, the target antigen should be abundant and accessible & should be expressed homogeneously, consistently and exclusively on the surface of cancer cells. • Mainly kills cells by complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) • Killing can result from direct action of the antibody, immune-mediated cell killing mechanisms, payload delivery, and specific effects of an antibody on the tumour vasculature and stroma Antibody Therapy • Ab therapy targets cancer antigents or Neoantigents • Ideally, the target antigen should be abundant and accessible & should be expressed homogeneously, consistently and exclusively on the surface of cancer cells. • Mainly kills cells by complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) • Killing can result from direct action of the antibody, immune-mediated cell killing mechanisms, payload delivery, and specific effects of an antibody on the tumour vasculature and stroma Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  24. 24. Ab Therapy • Naked monoclonal Abs – Antibodies without modification. Most of the currently used antibodies therapies are naked. • Conjugated monoclonal Abs – Abs are conjugated with toxins or radioactive compounds to properly deliver the conjugant Types of antibodies Two types of monoclonal antibodies used in therapy : Four types of monoclonal antibodies based on source: • Naked monoclonal Abs – Antibodies without modification. Most of the currently used antibodies therapies are naked. • Conjugated monoclonal Abs – Abs are conjugated with toxins or radioactive compounds to properly deliver the conjugant • Murine : antibodies were the first to be produced, and carry a great risk of immune reaction, because the antibodies are from a different species • Chimeric : the first attempt to reduce the immunogenicity. murine Abs with a specific constant region replaced with the corresponding human counterpart • Humanized : almost completely human; only the complementarity determining regions of the variable regions are derived from murine • Human antibodies have completely human origin Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.
  25. 25. Ab Therapy • Haematopoietic differentiation antigens – CD20, CD30, CD33, CD52 • Glycoproteins expressed by solid tumours – Mucins , EpCAM-epithelial cell adhesion molecule • Glycolipids – Gangliosides such as GD2, GD3 and GM2 • Carbohydrates – Lewis Y Ag expressed by 42% squamous cell lung carcinoma, 80% lung adenocarcinoma, 25% ovarian carcinoma, colorectal adenocarcinoma* • Targets of anti-angiogenic mAbs – Integrin α5β1 , VEGFR, VEGF • Growth and differentiation signalling – EGFR, ERBB2, ERBB3 • Stromal and extracellular matrix antigens – FAP-fibroblast activation protein Targets in Human Cancers • Haematopoietic differentiation antigens – CD20, CD30, CD33, CD52 • Glycoproteins expressed by solid tumours – Mucins , EpCAM-epithelial cell adhesion molecule • Glycolipids – Gangliosides such as GD2, GD3 and GM2 • Carbohydrates – Lewis Y Ag expressed by 42% squamous cell lung carcinoma, 80% lung adenocarcinoma, 25% ovarian carcinoma, colorectal adenocarcinoma* • Targets of anti-angiogenic mAbs – Integrin α5β1 , VEGFR, VEGF • Growth and differentiation signalling – EGFR, ERBB2, ERBB3 • Stromal and extracellular matrix antigens – FAP-fibroblast activation protein *The Lewis-Y carbohydrate antigen is expressed by many human tumors and can serve as a target for genetically redirected T cells despite the presence of soluble antigen in serum. Westwood.J.A Et.al 2009 Apr;32(3):292-301. doi: 10.1097/CJI.0b013e31819b7c8e.
  26. 26. Ab Therapy Mechanism of action • elicited by receptor agonist activity:- Ab binding to a tumour cell surface receptor and activating it, leading to apoptosis (represented by the mitochondrion). • by receptor antagonist activity:- Ab binding to a cell surface receptor and blocking dimerization, kinase activation and downstream signalling, leading to reduced proliferation and apoptosis. • An antibody binding to an enzyme can lead to neutralization, signalling abrogation & cell death, • conjugated antibodies can be used to deliver a payload (such as a drug, toxin, small interfering RNA or radioisotope) to a tumour cell. Direct Tumor cell Killing • elicited by receptor agonist activity:- Ab binding to a tumour cell surface receptor and activating it, leading to apoptosis (represented by the mitochondrion). • by receptor antagonist activity:- Ab binding to a cell surface receptor and blocking dimerization, kinase activation and downstream signalling, leading to reduced proliferation and apoptosis. • An antibody binding to an enzyme can lead to neutralization, signalling abrogation & cell death, • conjugated antibodies can be used to deliver a payload (such as a drug, toxin, small interfering RNA or radioisotope) to a tumour cell.
  27. 27. Ab Therapy Mechanism of action • can be carried out by the induction of •Phagocytosis; •Complement activation • Antibody-dependent cellular cytotoxicity (ADCC) • Genetically modified T cells being targeted to the tumour by single-chain variable fragment (scFv); T cells being activated by antibody-mediated cross- presentation of antigen to dendritic cells; and inhibition of T cell inhibitory receptors, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA4). Immune – mediated killing • can be carried out by the induction of •Phagocytosis; •Complement activation • Antibody-dependent cellular cytotoxicity (ADCC) • Genetically modified T cells being targeted to the tumour by single-chain variable fragment (scFv); T cells being activated by antibody-mediated cross- presentation of antigen to dendritic cells; and inhibition of T cell inhibitory receptors, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA4).
  28. 28. Ab Therapy Mechanism of action • Vascular and stromal cell ablation can be induced by •vasculature receptor antagonism or ligand trapping • stromal cell inhibition • delivery of a toxin to stromal cells • delivery of a toxin to the vasculature Vascular and stromal cell ablation • Vascular and stromal cell ablation can be induced by •vasculature receptor antagonism or ligand trapping • stromal cell inhibition • delivery of a toxin to stromal cells • delivery of a toxin to the vasculature
  29. 29. Ab Therapy • A human IgG4 anti-PD-1 monoclonal antibody developed by Ono Pharmaceutical and Medarex • inhibitory ligand blocking antibody against the programmed death receptor • PD-1 is a protein on the surface of activated T cells. If its is ligand PD-L1 or PD-L2, binds to PD-1, the T cell becomes inactive. • This is one way that the body regulates the immune system, to avoid an overreaction. • Many cancer cells make PD-L1, which inhibits T cells from attacking the tumor • nivolumab acts by blocking PD-1 of T-cell activation and response thus allowing the immune system to attack the tumor • Uses: Metastatic melanoma, Lung cancer, Hodgkin's lymphoma, Kidney cancer Examples | Nivolumab • A human IgG4 anti-PD-1 monoclonal antibody developed by Ono Pharmaceutical and Medarex • inhibitory ligand blocking antibody against the programmed death receptor • PD-1 is a protein on the surface of activated T cells. If its is ligand PD-L1 or PD-L2, binds to PD-1, the T cell becomes inactive. • This is one way that the body regulates the immune system, to avoid an overreaction. • Many cancer cells make PD-L1, which inhibits T cells from attacking the tumor • nivolumab acts by blocking PD-1 of T-cell activation and response thus allowing the immune system to attack the tumor • Uses: Metastatic melanoma, Lung cancer, Hodgkin's lymphoma, Kidney cancer
  30. 30. Ab Therapy Examples | Nivolumab
  31. 31. Ab Therapy • a chimeric monoclonal antibody against the protein CD20 • used to treat diseases which are characterized by excessive numbers of B cells, overactive B cells, or dysfunctional B cells. • Ex:- lymphomas, leukemias, transplant rejection, and autoimmune disorders. • CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation, but it is absent on terminally differentiated plasma cells. CD20 does not shed, modulate or internalise. Although the function of CD20 is unknown, it may play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells. Examples | Rituximab • a chimeric monoclonal antibody against the protein CD20 • used to treat diseases which are characterized by excessive numbers of B cells, overactive B cells, or dysfunctional B cells. • Ex:- lymphomas, leukemias, transplant rejection, and autoimmune disorders. • CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation, but it is absent on terminally differentiated plasma cells. CD20 does not shed, modulate or internalise. Although the function of CD20 is unknown, it may play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells.
  32. 32. Ab Therapy The following effects have been found: • The Fc portion of rituximab mediates ADCC and CDC • It increases MHC II and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen). • It elicits shedding of CD23. • It downregulates the B cell receptor. • It induces apoptosis of CD20+ cells. • The combined effect results in the elimination of B cells and allow production of healthy cells Examples | Rituximab The following effects have been found: • The Fc portion of rituximab mediates ADCC and CDC • It increases MHC II and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen). • It elicits shedding of CD23. • It downregulates the B cell receptor. • It induces apoptosis of CD20+ cells. • The combined effect results in the elimination of B cells and allow production of healthy cells
  33. 33. PET-CT scan showing localisation of 124I- labelled cG250 (carbonic anhydrase IX (CAIX)- specific) monoclonal antibody, obtained 5 days after antibody infusion. The specific uptake of the antibody can be seen in the left renal tumour (arrow), which is expressing CAIX antigen. PET-CT scan showing localisation of 124I- labelled cG250 (carbonic anhydrase IX (CAIX)- specific) monoclonal antibody, obtained 5 days after antibody infusion. The specific uptake of the antibody can be seen in the left renal tumour (arrow), which is expressing CAIX antigen.
  34. 34. Cytokines, secreted proteins with immunemodulating properties, can be delivered systemically to activate antitumor immunity Cytokine Therapy Cytokines, secreted proteins with immunemodulating properties, can be delivered systemically to activate antitumor immunity
  35. 35. • Cytokines are secreted or membrane-bound proteins • Significance in immuno survialence:- higher frequency of spontaneous cancers seen in mice genetically deficient in type I or II IFN receptors or elements of downstream IFN receptor signal transduction • IL-2 & IFN-α have been used to treat advanced melanoma & renal cell Cytokine Therapy • Cytokines are secreted or membrane-bound proteins • Significance in immuno survialence:- higher frequency of spontaneous cancers seen in mice genetically deficient in type I or II IFN receptors or elements of downstream IFN receptor signal transduction • IL-2 & IFN-α have been used to treat advanced melanoma & renal cell
  36. 36. • secreted by nearly every cell in the body and involved in cellular immune responses against viral infections • Type I-IFNs induce expression of MHC class I molecules on tumor cells and mediate the maturation of a subset of DC • can also activate CTLs, NK cells and macrophages • IFN- α is the only currently approved adjuvant therapy for patients with high-risk Stage II or Stage III melanoma • Also approved for the treatment of some hematologic malignancies, AIDS-related Kaposi’s sarcoma, and as a component in an anti-angiogenic combination regimen with bevacizumab for advanced renal cancer • IFN-α has dose related toxicity, can leads to depression, confusion, mania and other neuropsychiatric diseases. High doasages may coause permanaent alternation of immune system causing vitiligo and hypothyroidism Cytokine Therapy Type I Interferons IFN-α • secreted by nearly every cell in the body and involved in cellular immune responses against viral infections • Type I-IFNs induce expression of MHC class I molecules on tumor cells and mediate the maturation of a subset of DC • can also activate CTLs, NK cells and macrophages • IFN- α is the only currently approved adjuvant therapy for patients with high-risk Stage II or Stage III melanoma • Also approved for the treatment of some hematologic malignancies, AIDS-related Kaposi’s sarcoma, and as a component in an anti-angiogenic combination regimen with bevacizumab for advanced renal cancer • IFN-α has dose related toxicity, can leads to depression, confusion, mania and other neuropsychiatric diseases. High doasages may coause permanaent alternation of immune system causing vitiligo and hypothyroidism
  37. 37. • produced by leukocytes but also by some tumors • comparatively, IFN-β is more potent than IFN- α in inducing antiproliferative effects in cancer models • Usage is limitted due to substantial side effects Cytokine Therapy Type I Interferons IFN-β • produced by leukocytes but also by some tumors • comparatively, IFN-β is more potent than IFN- α in inducing antiproliferative effects in cancer models • Usage is limitted due to substantial side effects
  38. 38. • only member of this family is IFN-γ • role in immunosurveillance :mice with targeted deletion of IFN or the Type II IFN receptor have an increased risk of spontaneous and chemically-induced tumors compared to controls • cytotoxic to some malignant cells and has modest anti-angiogenic activity • IFN- has demonstrated very limited clinical utility in cancer therapy Cytokine Therapy Type II Interferons • only member of this family is IFN-γ • role in immunosurveillance :mice with targeted deletion of IFN or the Type II IFN receptor have an increased risk of spontaneous and chemically-induced tumors compared to controls • cytotoxic to some malignant cells and has modest anti-angiogenic activity • IFN- has demonstrated very limited clinical utility in cancer therapy
  39. 39. • IL-2 plays a pivotal role in the treatment of patients with metastatic melanoma and renal cell carcinoma. • National Cancer Institute found that adoptively transferred IL-2-activated peripheral blood mononuclear cells with administration of IL-2 in high doses, resulted in significant tumor regression in patients • it promotes both effector T cells and T-reg cells, but its exact mechanism in the treatment of cancer is unknown • Side effects: capillary leak syndrome, which is characterized by hypotension, tachycardia and peripheral edema secondary to third space fluid accumulation. • fever, chill and fatigue, gastrointestinal side effects such as nausea, vomiting, anorexia, cholestasis and diarrhea • IL-2 reported a 2% mortality rate Cytokine Therapy Interleukin-2 • IL-2 plays a pivotal role in the treatment of patients with metastatic melanoma and renal cell carcinoma. • National Cancer Institute found that adoptively transferred IL-2-activated peripheral blood mononuclear cells with administration of IL-2 in high doses, resulted in significant tumor regression in patients • it promotes both effector T cells and T-reg cells, but its exact mechanism in the treatment of cancer is unknown • Side effects: capillary leak syndrome, which is characterized by hypotension, tachycardia and peripheral edema secondary to third space fluid accumulation. • fever, chill and fatigue, gastrointestinal side effects such as nausea, vomiting, anorexia, cholestasis and diarrhea • IL-2 reported a 2% mortality rate
  40. 40. • When combined with vaccines, cytokines can boost immune responses through recruitment and maturation of a wider variety of immune effector cells • Ex:- GM-CSF primarily acts on myeloid cells, functions to recruit DCs • GVAX is a granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transfected tumor cell vaccine • GM-CSF gene transfected into tumor cells and used as a vaccine (GVAX). Tumor regression and prolonged survival was demonstrated in animal models. Toxicology with GVAX indicated no adverse effects, which enabled further testing in cancer patients. • GVAX a vaccines based on cytokine is currently in Phase II in pancreatic cancer, Aduro Biotech, a private company is also trialing a combination of GVAX with a PD-1 inhibitor Cytokine Based Tumor Cell Therapy • When combined with vaccines, cytokines can boost immune responses through recruitment and maturation of a wider variety of immune effector cells • Ex:- GM-CSF primarily acts on myeloid cells, functions to recruit DCs • GVAX is a granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transfected tumor cell vaccine • GM-CSF gene transfected into tumor cells and used as a vaccine (GVAX). Tumor regression and prolonged survival was demonstrated in animal models. Toxicology with GVAX indicated no adverse effects, which enabled further testing in cancer patients. • GVAX a vaccines based on cytokine is currently in Phase II in pancreatic cancer, Aduro Biotech, a private company is also trialing a combination of GVAX with a PD-1 inhibitor
  41. 41. Adaptive T cell therapy The initial T-cell based therapy was reported by Rosenberg in 1988
  42. 42. • isolate antigen-specific T cells from a cancer patient, expand them to large numbers in a test- tube, and re-infuse them back into the patient to kill off the remaining tumor cells • Cells are Harvested from a variety of sites, including peripheral blood, malignant effusions, resected lymph nodes, and tumor biopsies • tumor-infiltrating lymphocytes (TILs) obtained from biopsies may contain a higher frequency of tumor- reactive cells • T cells can be expanded through polyclonal stimulation with activating antibodies or through exposure to specific tumor antigens Adoptive T cell therapy • isolate antigen-specific T cells from a cancer patient, expand them to large numbers in a test- tube, and re-infuse them back into the patient to kill off the remaining tumor cells • Cells are Harvested from a variety of sites, including peripheral blood, malignant effusions, resected lymph nodes, and tumor biopsies • tumor-infiltrating lymphocytes (TILs) obtained from biopsies may contain a higher frequency of tumor- reactive cells • T cells can be expanded through polyclonal stimulation with activating antibodies or through exposure to specific tumor antigens
  43. 43. • Such infusions are short lived because immune system where not able to provide co-stimulatory signals to sudden large increase of CTLs • Also requires the identification of relevant targets • This can be overcome by treating the culture with co stimulatory molecules • CTL lines have cultured in medium containing IL-2 support T cell survival and proliferation • cytokines such as IL-7, IL-12, IL-15, and IL-21 have also proven crucial for the reactivation, survival, and expansion of tumor specific T cells in vitro • A second approach is by using genetic enginneering Adoptive T cell therapy • Such infusions are short lived because immune system where not able to provide co-stimulatory signals to sudden large increase of CTLs • Also requires the identification of relevant targets • This can be overcome by treating the culture with co stimulatory molecules • CTL lines have cultured in medium containing IL-2 support T cell survival and proliferation • cytokines such as IL-7, IL-12, IL-15, and IL-21 have also proven crucial for the reactivation, survival, and expansion of tumor specific T cells in vitro • A second approach is by using genetic enginneering
  44. 44. • T cells harvested from the peripheral blood can be engineered to express TCRs that have been selected for tumor recognition - tested in metastatic melanoma • because TCR recognition of antigen is MHC restricted, each engineered TCR can only be used in patients with the required MHC allele • This can be bypassed by engineering T cells to express novel chimeric fusion proteins, “T-bodies” that link the antigen-binding domain of the B cell receptor with the signaling component of the TCR complex. • T-bodies can directly bind tumor antigens, leading to T cell activation • tested in ovarian carcinoma, and pediatric neuroblastoma Adoptive T cell therapy • T cells harvested from the peripheral blood can be engineered to express TCRs that have been selected for tumor recognition - tested in metastatic melanoma • because TCR recognition of antigen is MHC restricted, each engineered TCR can only be used in patients with the required MHC allele • This can be bypassed by engineering T cells to express novel chimeric fusion proteins, “T-bodies” that link the antigen-binding domain of the B cell receptor with the signaling component of the TCR complex. • T-bodies can directly bind tumor antigens, leading to T cell activation • tested in ovarian carcinoma, and pediatric neuroblastoma
  45. 45. Adoptive T cell therapy Different approaches
  46. 46. Adoptive T cell therapy Before treatment Complete Regression of Metastatic Cervical Cancer After Treatment With Human Papillomavirus–Targeted Tumor-Infiltrating T Cells (HPV-TILs) May 10, 2015 After 22 months of treatment
  47. 47. Blockade of immune system inhibitory checkpoints to activates immune system function. Immune checkpoint blockade
  48. 48. • A particularly important immune-checkpoint receptor is cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), which downmodulates the amplitude of T cell activation. Antibody blockade of CTLA4 in mouse models of cancer induced antitumour immunity. • Clinical studies using antagonistic CTLA4 antibodies demonstrated activity in melanoma. Despite a high frequency of immune-related toxicity, this therapy enhanced survival in two randomized Phase III trials. • Anti-CTLA4 therapy was the first agent to demonstrate a survival benefit in patients with advanced melanoma and was approved by the US Food and Drug Administration (FDA) in 2010. • Nivolumab has been approved in 2014. Pembrolizumab was also approved by the FDA in 2014. • The first monoclonal antibody approved by the FDA for immune checkpoint blockade was ipilimumab, approved in 2011. Ipilimumab blocks the inhibitory immune checkpoint CTLA-4. Immune checkpoint blockade • A particularly important immune-checkpoint receptor is cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), which downmodulates the amplitude of T cell activation. Antibody blockade of CTLA4 in mouse models of cancer induced antitumour immunity. • Clinical studies using antagonistic CTLA4 antibodies demonstrated activity in melanoma. Despite a high frequency of immune-related toxicity, this therapy enhanced survival in two randomized Phase III trials. • Anti-CTLA4 therapy was the first agent to demonstrate a survival benefit in patients with advanced melanoma and was approved by the US Food and Drug Administration (FDA) in 2010. • Nivolumab has been approved in 2014. Pembrolizumab was also approved by the FDA in 2014. • The first monoclonal antibody approved by the FDA for immune checkpoint blockade was ipilimumab, approved in 2011. Ipilimumab blocks the inhibitory immune checkpoint CTLA-4.
  49. 49. Regressions of lung (top two panels) and brain (lower panel) metastases in a patient with melanoma who was treated with ipilimumab. 25–30% of patients treated with extended doses of anti-CTLA4 therapy can develop immune-related ‘on-target’ toxicities. However, the frequency of severe adverse toxicities was lower (10–15%) with the short course that was used in the Phase III trial that led to the approval of ipilimumab. This short-course regimen (4 doses at a cost of US$30,000 per dose) was recommended by the US Food and Drug Administration (FDA). Regressions of lung (top two panels) and brain (lower panel) metastases in a patient with melanoma who was treated with ipilimumab. 25–30% of patients treated with extended doses of anti-CTLA4 therapy can develop immune-related ‘on-target’ toxicities. However, the frequency of severe adverse toxicities was lower (10–15%) with the short course that was used in the Phase III trial that led to the approval of ipilimumab. This short-course regimen (4 doses at a cost of US$30,000 per dose) was recommended by the US Food and Drug Administration (FDA).
  50. 50. efficacy might be improved by combining [targeted] therapies with immune- stimulating agents Combined Therapy efficacy might be improved by combining [targeted] therapies with immune- stimulating agents
  51. 51. • monoclonal antibody trastuzumab targets ERBB2 in breast cancer and expose them to ADCC which depends on NK cells • Ronald Levy and colleagues investigated whether activation of the co-stimulatory molecule CD137 (also known as TNFRSF9 and 4-1BB) in NK cells could improve trastuzumab efficacy. • In vitro studies showed that co-incubation of ERBB2-expressing breast cancer cell lines and purified human NK cells with trastuzumab upregulated CD137 on the NK cells. • These activated NK cells were able to kill trastuzumab- coated ERBB2-expressing breast cancer cell lines through ADCC, and this was enhanced by a CD137 agonistic antibody. Combination of therapy • monoclonal antibody trastuzumab targets ERBB2 in breast cancer and expose them to ADCC which depends on NK cells • Ronald Levy and colleagues investigated whether activation of the co-stimulatory molecule CD137 (also known as TNFRSF9 and 4-1BB) in NK cells could improve trastuzumab efficacy. • In vitro studies showed that co-incubation of ERBB2-expressing breast cancer cell lines and purified human NK cells with trastuzumab upregulated CD137 on the NK cells. • These activated NK cells were able to kill trastuzumab- coated ERBB2-expressing breast cancer cell lines through ADCC, and this was enhanced by a CD137 agonistic antibody.
  52. 52. Combining PROSTVAC With ipilimumab
  53. 53. Combining PROSTVAC With radiotherapy Exposure of prostate cancer cell lines to 153Sm results in increased susceptibility to killing by cytotoxic T lymphocytes (CTLs), establishing a potential rationale for the combination of active immunotherapy with PROSTVAC and radiotherapy with 153Sm. Early clinical evidence is suggestive of potential clinical benefit with this combination. Exposure of prostate cancer cell lines to 153Sm results in increased susceptibility to killing by cytotoxic T lymphocytes (CTLs), establishing a potential rationale for the combination of active immunotherapy with PROSTVAC and radiotherapy with 153Sm. Early clinical evidence is suggestive of potential clinical benefit with this combination.
  54. 54. Reference • Cancer immunotherapy via dendritic cells, Karolina.P and Jacques.B, Focus on tumour immunology & immunotherapy, Nature reviews, cancer vol12, April 2012, p265-277© 2012 Macmillan Publishers Limited • Antibody therapy of cancer Andrew M. Scott1, Jedd D. Wolchok and Lloyd J. Old Nature Reviews, April 2012, Vol 12, p278-287 © 2012 Macmillan Publishers Limited. All rights reserved • Cytokines in Cancer Immunotherapy, Sylvia. L and Kim.M, Cancers 2011, Vol3, 3856-3893; doi:10.3390/cancers3043856, ISSN 2072-6694, www.mdpi.com/journal/cancers • Vaccines in cancer: GVAX, a GM-CSF gene vaccine, Nemunaitis J, Expert Rev Vaccines. 2005 Jun;4(3):259-74 • Complete Regression of Metastatic Cervical Cancer After Treatment With Human Papillomavirus–Targeted Tumor-Infiltrating T Cells , Sanja Stevanović et al, American Society of Clinical Oncology, May 10, 2015 vol. 33 no. 14 1543-1550 , doi: 10.1200/JCO.2014.58.9093 • Combinations that work, Sarah Seton-Rogers, Research Highlights Nature Reviews, Cancer Vol12, APRIL 2012 • Cancer immunotherapy via dendritic cells, Karolina.P and Jacques.B, Focus on tumour immunology & immunotherapy, Nature reviews, cancer vol12, April 2012, p265-277© 2012 Macmillan Publishers Limited • Antibody therapy of cancer Andrew M. Scott1, Jedd D. Wolchok and Lloyd J. Old Nature Reviews, April 2012, Vol 12, p278-287 © 2012 Macmillan Publishers Limited. All rights reserved • Cytokines in Cancer Immunotherapy, Sylvia. L and Kim.M, Cancers 2011, Vol3, 3856-3893; doi:10.3390/cancers3043856, ISSN 2072-6694, www.mdpi.com/journal/cancers • Vaccines in cancer: GVAX, a GM-CSF gene vaccine, Nemunaitis J, Expert Rev Vaccines. 2005 Jun;4(3):259-74 • Complete Regression of Metastatic Cervical Cancer After Treatment With Human Papillomavirus–Targeted Tumor-Infiltrating T Cells , Sanja Stevanović et al, American Society of Clinical Oncology, May 10, 2015 vol. 33 no. 14 1543-1550 , doi: 10.1200/JCO.2014.58.9093 • Combinations that work, Sarah Seton-Rogers, Research Highlights Nature Reviews, Cancer Vol12, APRIL 2012

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