Immunotherapy
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The document discusses immunotherapy as a treatment that leverages the immune system to combat diseases like cancer, tracing its origins to Dr. William B. Coley's work with bacteria-injected tumor treatments. It outlines three main methods being researched: enhancing tumor cell immunogenicity, employing passive immunity via monoclonal antibodies and immunotoxins, and stimulating immune response through vaccines. The document provides examples of various immunotherapeutic approaches, including immune checkpoint inhibitors, adoptive cellular transfer, and cancer vaccines, underscoring their mechanisms and potential clinical applications.
Immunotherapy
- 2. INTRODUCTION 8/26/20162 Treatment that uses certain parts of the immune system to fight against diseases such as cancer. Basic aim of immunotherapy is to enhance the immune response to tumours in the host. Immunotherapy is a cancer treatment more than 100 years in the making, beginning most notably with Dr. William B. Coley, who worked with patients and multiple doctors to study how cancer tumors reacted to infections.
- 3. 8/26/20163 He treated cancer patients with inoperable tumors by injecting a combination of bacteria, which became known as Coley’s Toxins, directly into their tumors. His results showed that this treatment shrank the tumors and sometimes even cured the patient. He believed that the body’s increased response to the bacteria also helped fight off the cancer.
- 4. 8/26/20164 Three approaches are being tried currently : A. 1.Increasing the immunogenicity of tumour cells so that they themselves lead to a strong immune response B. 2.Enhance the passive immunity against cancers by use of monoclonal antibodies or adoptive cellular immunotherapy C. 3.Stimulation of the immune system by cancer vaccines e.g. Active immunization against cancer
- 5. (A)ENHANCEMENT OF TUMOUR CELL IMMUNOGENICY 8/26/20165 This is done in several ways : 1.Making tumour cell capable of providing Co- stimulatary signal Most tumour cells do not provide co- stimulatory signal because they are unable to stimulate T-cells. It is seen that melanoma cells,transfected with B-7 gene,on incubation with CTL-Ps,leads to their differentiation into CTLs. Subsequently ,when animals with melanoma tumours
- 6. 8/26/20166 were injected with B7+ melanoma cells,40% of the animals shows complete regression of tumour.
- 7. 8/26/20167 2.Making tumour cells to act as good APCs By enhancing the presence of APCs around the tumour cells,so that they capture tumour antigen ,stimulate TH cells and generate CTLs specific to tumour antigens These CTLs are then expected to kill the tumour cells.
- 8. 8/26/20168 GM-CSF has been found to enhance the differentiation and APC activity of the dendritic cells. Using this principle,tumour cells transfected with GM-CSF gene,on reinfusion into patients,secrete GM-CSF which enhance dendritic cell population around tumour and enhance their APC activity.
- 9. 8/26/20169 This lead to developement of tumour specific CTLs and cellular immunity against the tumour.
- 10. 8/26/201610 Alternate approach is to obtain population of dendritic cells and grow them in invitro culture in the presence of GM-CSF ,TNF-α and IL-4 and tumour fragments to sensitize them to tumour antigens. Then on injection into patients, they are expected to mount a strong cell mediated response. This is under investigation.
- 11. 8/26/201611 3.USE OF CYTOKINES Various cytokines are known to augment the immune response by acting at various stages of cell differetiation and its immune function. E.g . TNF-α,β and γ,IL-1,2,4,5 and 12, GM- CSF and TNF. Use of cytokines as drugs for systemic use in treatment against diseases including cancers is loaded with serious problem that prevent their widespread use at present.
- 12. 8/26/201612 INTERFERONS They enhance tumour immune response by three mechanisms: A. They increase MHC-I expression on tumour cells,so it is likely to restore their APC activity which leading to activate CTLs causing tumour cell killing. IFN-γ ehnances MHC-II expression So they together will increase the overall tumour cell immunogenicity.
- 13. 8/26/201613 B. IFN-γ increases activity of cytotoxic cells e.g. Tc cells, macrophages and NK cells They will augment the cell mediated response against tumour. C. They also inhibit the cell mitosis in both normal and cancerous cells. Together all three actions increases the overall antitumour cellular immunity in the host.
- 14. 8/26/201614 TUMOUR NECROSIS FACTOR (TNF) : TNF-α and β shown to induce visible hemorrhagic necrosis and tumour regression TNF-α inhibit the tumour induced vascularisation by damaging the vascular endothelial cells. This deprives the tumour of essential nutrients and O2 leading to necrosis and regression.
- 15. (B)PASSIVE IMMUNOTHERAPY OF CANCER 8/26/201615 Tumour specific immuno effector molecules or cells are injected into the patients. Monoclonal antibodies to specific tumour antigens and immunotoxins are being tried. MONOCLONAL ANTIBODIES : Antiidiotypic monoclonal antibodies have been tried in B-cell lymphoma. Such antibodies on injection ,will bind to cancerous B-cells and activate the complement mediated lysis of the cancerous cell.
- 16. 8/26/201616 IMMUNOTOXINS : These are monoclonal antibodies combined to some antitumor toxic agents like radiation source,anticancer drugs or potent biological toxins etc. They kill tumours in highly specific manner. Immunotoxins against melanomas,breast cancer,colorectal cancer are already undergoing phase I and phase II clinical trials with encouraging results.
- 17. 8/26/201617
- 18. 8/26/201618 Radiolabeled antibodies: Radiolabeled antibodies have small radioactive particles attached to them. Ibritumomab tiuxetan (Zevalin® ) is an example of a radiolabeled mAb. This is an antibody against the CD20 antigen, which is found on lymphocytes called B cells. The antibody delivers radioactivity directly to cancerous B cells and can be used to treat some types of non-Hodgkin lymphoma.
- 19. 8/26/201619 Chemolabeled antibodies: These mAbs have powerful chemotherapy (or other) drugs attached to them. They are also known as antibody-drug conjugates (ADCs). The drug is often too powerful to be used on its own – it would cause too many side effects if not attached to an antibody.
- 20. 8/26/201620 Chemolabeled antibodies used to treat cancer include: 1)Brentuximab vedotin (Adcetris® ) : o An antibody that targets the CD30 antigen (found on lymphocytes), attached to a chemo drug called MMAE. o This drug is used to treat Hodgkin lymphoma and anaplastic large cell lymphoma..
- 21. 8/26/201621 2)Ado-trastuzumab Emtansine (Kadcyla® ) o An antibody that targets the HER2 protein. o It’s used to treat some breast cancer patients whose cancer cells have too much HER2.
- 22. BISPECIFIC MONOCLONAL ANTIBODIES 8/26/201622 These drugs are made up of parts of 2 different mAbs, meaning they can attach to 2 different proteins at the same time. An example is blinatumomab (Blincyto), which is used to treat some types of acute lymphocytic leukemia (ALL). One part of blinatumomab attaches to the CD19 protein, which is found on some leukemia and lymphoma cells.
- 23. 8/26/201623 Another part attaches to CD3, a protein found on T-cells. By binding to both of these proteins, this drug brings the cancer cells and immune cells together, which is thought to cause the immune system to attack the cancer cells.
- 24. IMMUNE CHECKPOINT INHIBITORS TO TREAT CANCER 8/26/201624 An important part of the immune system is its ability to tell between normal cells in the body and those it sees as “foreign.” This lets the immune system attack the foreign cells while leaving the normal cells alone. To do this, it uses “checkpoints” – molecules on certain immune cells that need to be activated (or inactivated) to start an immune response.
- 25. 8/26/201625
- 26. 8/26/201626 Cancer cells sometimes find ways to use these checkpoints to avoid being attacked by the immune system. Drugs that target PD-1 or PD-L1 : PD-1 is a checkpoint protein on T cells. It normally acts as a type of “off switch” that helps keep the T cells from attacking other cells in the body.
- 27. 8/26/201627 It does this when it attaches to PD-L1, a protein on some normal (and cancer) cells. When PD-1 binds to PD-L1, it basically tells the T cell to leave the other cell alone. Some cancer cells have large amounts of PD-L1, which helps them evade immune attack. Monoclonal antibodies that target either PD-1 or PD-L1 can boost the immune response against cancer cells.
- 28. 8/26/201628 PD-1 inhibitors: Examples of drugs that target PD-1 include: • Pembrolizumab (Keytruda) • Nivolumab (Opdivo) o These drugs have been shown to be helpful in treating several types of cancer : • Melanoma Of The Skin, • Non-small Cell Lung Cancer, • Kidney Cancer And Hodgkin Lymphoma.
- 29. 8/26/201629 PD-L1 inhibitors: An example of a drug that targets PD-L1 is: Atezolizumab (Tecentriq) This drug can be used to treat bladder cancer, and is also being studied for use against other types of cancer. One concern with all of these drugs is that they can allow the immune system to attack some normal organs in the body, which can lead to serious side effects in some people.
- 30. 8/26/201630 Drugs that target CTLA-4 : CTLA-4 is another protein on some T cells that acts as a type of “off switch” to keep the immune system in check. Ipilimumab (Yervoy) is a monoclonal antibody that attaches to CTLA-4 and stops it from working. This can boost the body’s immune response against cancer cells. This drug is used to treat melanoma of the skin.
- 31. ADOPTIVE CELLULAR TRANSFER 8/26/201631 Administration of in vitro activated killer cells- lymphocytes and NK cells into cancer patients. These activated cells enhance tumour cell killing. Lymphokines activated killer cells (LAK-cells) and Tumour infiltrating lymphocytes (TILs) have been tried.
- 32. 8/26/201632 LAK-cells : In the presence of high concentrations of IL- 2,peripheral lymphocytes are converted into killer cells called lymphokines activated killer cells (LAK-cells) which display high level of antitumour activity. Most LAK cells (90%) are derived from NK- cells.
- 33. 8/26/201633 In human beings it is tried in stage IV metastatic cancers with some success,but serious side effects also. Vascular leak syndrome : Lymphoid cells and plasma migrate from the vessels into tissues leading to shock.
- 34. 8/26/201634 TIL : They behave and resemble LAK cells in their anti tumour activity They are lymphocytes that infiltrate tumour in vivo. After obtaining from tumour samples, in vitro cultures done with high doses of IL-2 done.
- 35. 8/26/201635 On administration,these require much lower IL-2 dose than LAK cells (100 times less). This has been tried in renal cell carcinoma patients and malignant melanoma patients with 20-30% success rate of partial regression.
- 36. 8/26/201636 On administration,these require much lower IL-2 dose than LAK cells (100 times less). This has been tried in renal cell carcinoma patients and malignant melanoma patients with 20-30% success rate of partial regression.
- 37. (C)CANCER VACCINES 8/26/201637 Host tumours contain many unique antigens which are recognized by T-cells and lead to production of tumour specific CTLs. Patients own tumour cells or cell extracts were used initially as potential immunizing agents or vaccines. Two approaches are used : 1. MHC molecules are isolated from the tumour cells and mixture of peptides bound to them are eluted,purified and tested individually to detect the best immunogenic peptide.
- 38. 8/26/201638 Its structure is then determined for use as antigens. 2. DNA made out of tumour cells,is transfected into MHC-I expressing cells These cells are then tested for their ability to stimulate tumour specific CTL-response. The protein encoded by transfected gene on the cells is identified and its antigenic fragment detected and sequenced. Intact protein administered as to be complexed with MHC-II molecules on APCs after processing.
- 39. 8/26/201639 Administration of DNA through a vector seems viable as the DNA would be taken up by the cells and translated into proteins in the cytoplasm and then expressed on cell surface in the combination with MHC-I.
- 40. 40 TYPES OF VACCINES Tumor cell vaccines actual cancer cells Antigen vaccines only one antigen Dendritic cell vaccines DNA vaccines
- 41. VECTOR - BASED VACCINES 8/26/201641 Vector-based vaccines are made from altered viruses or bacteria that are injected into the body to create an immune response, both specific and overall. Tumor-specific vectors are genetically modified to target specific cancer cells in such a way that trains the immune system to recognize and destroy them Oncolytic virus immunotherapy uses natural or modified viruses to directly attack and kill tumor cells
- 42. 8/26/201642 One of the most-studied approaches uses a modified, weakened version of the herpes simplex virus called Talimogene Laherparepvec (TVEC). TVEC is a safer herpes virus that contains the gene for GM-CSF. The virus targets only specific cancer cells, infects them and replicates continuously within the cell until it explodes.
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- 44. Sipuleucel-T (Provenge® ) 8/26/201644 This is the only vaccine approved in the US to treat cancer so far. It’s used to treat advanced prostate cancer that is no longer being helped by hormone therapy. For this vaccine, immune system cells are removed from the patient’s blood and sent to a lab. There they are exposed to chemicals that turn them into special immune cells called dendritic cells.
- 45. 8/26/201645 They are also exposed to a protein called prostatic acid phosphatase (PAP), which should produce an immune response against prostate cancer cells. The dendritic cells are then given back to the patient by infusion into a vein (IV). This process is repeated twice more, 2 weeks apart, so that the patient gets 3 doses of cells. Back in the body, the dendritic cells help other immune system cells attack the prostate cancer.
- 46. REFERENCES 8/26/201646 Dr.S.K.Gupta ,Textbook of essential of Immunology,2nd edition. Thao Doan,Roger Melvold,Lippincott’s illustrated reviews of Immunology,2nd Edition. Google images.
- 47. Thank You