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Cancer Immunotherapy
- 1. Molecular Basis of Disease April 21st, 2016 Presented by Thi Tran-Nguyen kimthi@uab.edu
- 2. Growth of publications about âcancer immunotherapyâ Science 20 December 2013: Vol. 342 no. 6165 http://www.genengnews.com/insight-and-intelligence/cancer-immunotherapy- 2016/77900623/
- 3. Outline ⢠Tumor-Immune system interactions ⢠Cancer Immunotherapy ⢠Challenges in Immunotherapy
- 4. Immune responses can be anti-tumor or pro-tumor development
- 5. Chronic Inflammation can give rise to cancer Cell. 2010 March 19; 140(6): 883â899.
- 6. Chronic Inflammation can give rise to cancer Cell. 2010 March 19; 140(6): 883â899.
- 7. Andrea B. Apolo at Genitouri Cancer Symposium
- 8. Abbas et al : Cellular and Molecular Imm. 8th ed. Lymphocytic Infiltration to Tumor sites
- 16. Passive Non-specific Immunotherapy: Immune checkpoint blockade Ipilimumab (Yervoy) ⢠mAb to block CTLA-4 ⢠FDA-approved to treat melanoma 2011 ⢠~$130.000/treatment ⢠Severe immunological affects due to massive T cell activation Nivolumab (Opdivo) ⢠mAb to block PD-1 ⢠FDA-approved to treat melanoma 2014 and SNLC 2015 ⢠~$110.000/treatment ⢠Severe immunological affects due to massive T cell activation
- 17. Immune checkpoint blockade Nivolumab plus Ipilumab in advanced melanoma
- 20. Active Non-specific Immunotherapy- BCG Vaccine ⢠1921, Bacillus Calmette-GuÊrin (BCG)- a live attenuated strain of Mycobacterium Bovis was developed. ⢠1929, Pearl et al noted lower frequency of cancer among TB patients. ⢠1969, Mathe et al demonstrated remission in ALL in 12 out of 20 patients treated with BCG. ⢠1971, Zebar et al noted suppression of tumor growth at site of tumor inoculated with BCG. ⢠1974, Morten et al demonstrated regression in metastatic melanoma skin lesion injected with BCG. ⢠1976, Morales et al was the first to use intravesical BCG. ⢠Nowadays, BCG induction + maintenance therapy is and has been the predominant therapy for non-muscle invasive bladder cancer for ~40 years.
- 21. Active Non-specific Immunotherapy- BCG Vaccine administration Catheters used in intra-vesicle immunotherapy
- 22. Active Non-specific Immunotherapy- BCG Vaccine for non-muscular-invasive-bladder cancer
- 23. Active Non-specific Immunotherapy- BCG Vaccine for non-muscular-invasive-bladder cancer Efficacy: ⢠5 year recurrence free survival 60% ⢠27% reduction in progression compared to other intravesical therapies ⢠Best therapy suggested for bladder cancer. Good response requires: ⢠Immuno-competent host ⢠Small tumor burden ⢠Adequate dose to incite reaction ⢠BCG successfully infect urothelial cells ⢠BCG does not become virulent by mutational drift
- 25. Specific Immunotherapy Ideal Tumor antigen? ⢠Inherently immunogenic, capable of eliciting strong T- cell mediated immunity ⢠Expressed in a high % of tumors ⢠Uniform expression throughout tumor â˘Restricted expression in normal tissues â˘Functionally important for tumor cell survival â˘Does not have to be membrane associated
- 27. Passive specific Immunotherapy ⢠Ab directed to Tumor Ag
- 29. Passive specific Immunotherapy Ab directed to Tumor Ag
- 30. Passive specific Immunotherapy Anti-HER2 antibodies approved for late stage breast cancer Ann Transl Med. 2014 Dec; 2(12): 122.
- 31. Passive specific Immunotherapy CAR-T cells
- 32. Passive specific Immunotherapy CAR-T cell Abbas et al : Cellular and Molecular Imm. 8th ed.
- 34. https://www.youtube.com/watch?v=Sz11e0r2L_s Emilyâs Story: A young girl beats cancer with immunotherapy
- 36. Emilyâs Story: A young girl beats cancer with immunotherapy
- 37. Non- specific Specific Immunotherapy Passive ActivePassive Active Tumor Vaccine ⢠In situ Vaccines ⢠Cell-based Vaccines ⢠Dendritic cellâbased Vaccines ⢠Nonâcell-based Vaccines
- 38. Tumor antigen administered as: - DNA - recombinant proteins or peptides - recombinant viruses - autologous tumor protein extract - total autologous tumor mRNA Immunization with dendritic cells. âş Dendritic cells are highly efficient APCs that play a key role in the recognition of tumor antigens in vivo. âş Immunization with dendritic cells genetically modified to express tumor antigen or pulsed with peptide antigens induces vigorous immune responses. Dr. Helâs slides
- 39. Dendritic cell-the key sentinel who has unparalleled capacity to activate naĂŻve T cells.
- 41. PROVENGEÂŽ(sipuleucel-T) is approved by the FDA as an autologouscellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic hormone refractory prostate cancer.
- 43. Active Specific Immunotherapy-Cancer Vaccine http://dealbook.nytimes.com/2014/11/10/dendreon-maker-of-prostate-cancer-drug- provenge-files-for-bankruptcy/?_r=0
- 45. ⢠Specific immunotherapy: ď Is the targeted tumor antigen good enough? ď Tumor-resistance ⢠Non Specific Immunotherapy: ď How to ensure that the provoked immune response are specifically against the tumor? ď Autoimmunity ⢠Passive Immunotherapy: ď Tumor-resistance to tumor-specific ab treatment and CAR-T Cells ⢠Active Immunotherapy: ď Requires good autologous immune responses ď DC vaccines: Necessitates more understanding about the complex biology of DCs Challenges in Cancer immunotherapy
- 46. ďCancer immunotherapy is usually the last resort when all have failed. ďśTumor has been immune-sculpted to be non-immunogenic. ďśImmuno-suprressive, chronically inflamed individuals ďśChemotherapy/radiation therapy weakened immune system ďśCachexia ďCancer immunotherapy is expensive and is not one-size-fit-all. ď New emerging therapy-> new FDA regulations-> new criteria for prognostic and evaluation of efficacy. Challenges in Cancer immunotherapy
- 47. âAlthough the way ahead [for immunology] is full of pitfalls and difficulties, this is indeed an exhilarating prospect. There is no danger of a shortage of forthcoming excitement in the subject. Yet, as always, the highlights of tomorrow are the unpredictabilities of today.â From Nobel Lecture (8 Dec 1984, Nobel Lectures in Physiology Or Medicine: 1981-1990 (1993), 267. â CĂŠsar Milstein
Editor's Notes
- Figure 1 presents the number of publications in the cancer immunotherapy space in a given year. Note the growth of this space, which in recent years has gone exponential.
- Cellular Plasticity (T cells, DCs) =>Homeostasis AIDS patients and transplant recipients on immunosuppressive drugs have a much higher incidence of several types of cancer than do individuals with fully competent immune systems
- Types of inflammation in tumorigenesis and cancer. Chronic inflammation associated with infections or autoimmune disease precedes tumor development and can contribute to it through induction of oncogenic mutations, genomic instability, early tumor promotion, and enhanced angiogenesis. Prolonged exposure to environmental irritants or obesity can also result in low-grade chronic inflammation that precedes tumor development and contributes to it through the mechanisms mentioned above. Tumor-associated inflammation goes hand in hand with tumor development. This inflammatory response can enhance neo-angiogenesis, promote tumor progression and metastatic spread, cause local immunosuppression, and further augment genomic instability. Cancer therapy can also trigger an inflammatory response by causing trauma, necrosis, and tissue injury that stimulate tumor re-emergence and resistance to therapy. However, in some cases, therapy-induced inflammation can enhance antigen presentation, leading to immune-mediated tumor eradication. Tumor promoting mechanisms are in red and anti-tumorigenic mechanisms are in green. Note: Cancer can drive chronic inflammation and further enhance tumor development like a feed forward mechanism. In fact, chronic inflammation has long been recognized as a risk factor for development of tumors in many different tissues, especially those affected by chronic inflammatory diseases such as Barrettâs esophagus, Crohnâs disease, and ulcerative colitis, for example. Some cancers associated with infections are also considered to be an indirect result of the carcinogenic effects of the chronic inflammatory states that are induced by the infectious organisms. These include gastric carcinoma and lymphoma in the setting of chronic Helicobacter pylori infection and hepatocellular carcinomas associated with chronic hepatitis B and C virus infections. Although the mechanisms by which chronic inflammation can promote tumor development are not well understood, there are several possibilities, supported by data in rodent models.
- In fact, chronic inflammation has long been recognized as a risk factor for development of tumors in many different tissues, especially those affected by chronic inflammatory diseases such as Barrettâs esophagus, Crohnâs disease, and ulcerative colitis, for example. Some cancers associated with infections are also considered to be an indirect result of the carcinogenic effects of the chronic inflammatory states that are induced by the infectious organisms. These include gastric carcinoma and lymphoma in the setting of chronic Helicobacter pylori infection and hepatocellular carcinomas associated with chronic hepatitis B and C virus infections. Although the mechanisms by which chronic inflammation can promote tumor development are not well understood, there are several possibilities, supported by data in rodent models.
- AIDS patients and transplant recipients on immunosuppressive drugs have a much higher incidence of several types of cancer than do individuals with fully competent immune systems
- fTumor cells (especially spontaneous tumors) are weakly antigenic: mostly resemble host cells with a few tumor-specific ags. Rapid tumor growth overwhelm immune system (Canât eliminate all). Immune attack âsculptâ the formation of new tumors who have specialized mechanism to evade immune response.
- Immunoediting Both Protects Against and Promotes Tumor Growth
- Active immunotherapy is used to provoke the immune system into attacking the tumor cells by targeting tumour-associated antigens (TAAs). Passive immunotherapies are intrinsically functional and include monoclonal antibodies, lymphocytes, and cytokines. Among these, antibody therapies are the most successful to date and treat a wide range of cancers
- Active immunotherapy is used to provoke the immune system into attacking the tumor cells by targeting tumour-associated antigens (TAAs). Passive immunotherapies are intrinsically functional and include monoclonal antibodies, lymphocytes, and cytokines. Among these, antibody therapies are the most successful to date and treat a wide range of cancers
- is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system. (BLOCK inhibitory molecultes) pilimumab was approved by US FDA in March 2011 to treat patients with late-stage melanoma that has spread or cannot be removed by surgery Yervoy costs 4000 times more than gold!
- Panel B shows a representative waterfall plot of the maximum percentage change in target lesions, as compared with baseline measurements, in patients who received the concurrent regimen. A total of 47 patients had a response that could be evaluated in this analysis; 46 had a positive or negative change in target lesions from baseline, and 1 had no change. The dashed line denotes 80% tumor reduction in target lesions from baseline.
- Active immunotherapy is used to provoke the immune system into attacking the tumor cells by targeting tumour-associated antigens (TAAs). Passive immunotherapies are intrinsically functional and include monoclonal antibodies, lymphocytes, and cytokines. Among these, antibody therapies are the most successful to date and treat a wide range of cancers
- Non-Specific Stimulation of the Immune System Augmentation of Host Immunity to Tumors with Cytokines Cytokines that stimulate T cells and NK cells proliferation and differentiation.
- acute lymphoblastic leukemia
- acute lymphoblastic leukemia
- Active immunotherapy is used to provoke the immune system into attacking the tumor cells by targeting tumour-associated antigens (TAAs). Passive immunotherapies are intrinsically functional and include monoclonal antibodies, lymphocytes, and cytokines. Among these, antibody therapies are the most successful to date and treat a wide range of cancers
- Draw back of specific immunotherapy: tumor will down regulate the specific molecule and escape immune attack=> solution: Coctail=> target more than one molecule.
- Active immunotherapy is used to provoke the immune system into attacking the tumor cells by targeting tumour-associated antigens (TAAs). Passive immunotherapies are intrinsically functional and include monoclonal antibodies, lymphocytes, and cytokines. Among these, antibody therapies are the most successful to date and treat a wide range of cancers
- The potential of using antibodies as magic bullets has been alluring to investigators for many years and is still an active area ofresearch. Anti-tumor antibodies may eradicate tumors by the same effector mechanisms used to eliminate microbes, including opsonization and phagocytosis, activation of the complement system, and antibody-dependent cellular cytotoxicity.
- This approach requires covalent coupling of the toxin (lacking its cell-binding component) to an anti-tumor antibody molecule without loss of toxicity or antibody specificity. The systemically injected immunotoxin is endocytosed by tumor cells, and the toxin part is delivered to its intracellular site of action. Several practical difficulties must be overcome for this technique to be successful. The specificity of the antibody must be such that it does not bind to nontumor cells. A sufficient amount of antibody must reach the appropriate tumor target before it is cleared from the blood by Fc receptorâbearing phagocytic cells. The toxins, drugs, or radioisotopes attached to the antibody may have systemic effects as a result of circulation through normal tissues. For example, hepatotoxicity and vascular leak syndromes are common problems with immunotoxin therapy. Administration of immunotoxins may result in antibody responses against the toxins and the injected antibodies. Because of these practical difficulties, clinical trials of
- Currently, there are more than 100 different monoclonal antibodies being considered as therapeutic agents for cancer, either in experimental animal studies or in human trials, and a few have been approvedfor clinical use.These mechanisms are likely at work in B cell lymphoma patients treated with anti-CD20, one of the most successful anti-tumor antibody treatments to date A monoclonal antibody specific for the oncogene product HER2/Neu is an approved treatment for breast cancer patients whose tumors express high levels of the protein. In addition to eliciting immune effector mechanisms, the antiâHER2/ Neu antibody interferes with growth-signaling functions of the HER2/Neu molecule
- Schematic of the binding sites on human epidermal growth factor receptor 2 (HER2) for FDA-approved HER2-directed therapies. HER2 is a transmembrane receptor. Activation of HER2 results in cell signaling through the MAPK (RAS, RAF, MEK, and ERK) pathway and PI3K/Akt/mTOR pathways, leading to cellular proliferation. Trastuzumab and T-DM1 binds to the juxtamembrane domain of HER and inhibits cell signaling. T-DM1 is then endocytosed and DM-1 is released within the cell, where it can exert its cytotoxic effect via inhibiting microtubule function. In contrast pertuzumab binds domain II of the extracellular domain of HER2, preventing receptor heterodimerization with HER1, HER3, and HER4, and cell signaling. The tyrosine kinase inhibitor lapatinib binds the intracellular adenosine triphosphate binding domain of HER1 and HER2 and results in inhibition of cell signaling.
- therapy. Lymphocytes isolated from the blood or tumor infiltrate of a patient may be expanded by culture in IL-2 and infused back into the patient (A). The lymphocytes may be transfected with CAR genes (B). This treatment, often combined with systemic IL-2 administration, leads to tumor regression in some patients. In some cases, the patientâs T cells may be genetically transduced ex vivo to express recombinant chimeric antigen receptors (CARs) before transfer back into the patient. CARs (B) are composed of receptor domains specific for tumor antigens, and signaling domains, such as ITAMs and cytosolic motifs of CD28, which promote robust T cell activation.
- Active immunotherapy is used to provoke the immune system into attacking the tumor cells by targeting tumour-associated antigens (TAAs). Passive immunotherapies are intrinsically functional and include monoclonal antibodies, lymphocytes, and cytokines. Among these, antibody therapies are the most successful to date and treat a wide range of cancers
- Overall, the results of trials with many different types of tumor vaccines have been inconsistent, and this likely reflects the fact that one of the hallmarks of cancer is to evade host immunity. Tumors often do this by inhibiting immune responses. Most tumor vaccines are therapeutic vaccines; they have to be given after the host has encountered the tumor (unlike preventive vaccines for infections), and in order to be effective, they have to overcome the immune regulation that cancers establish. The development of virally induced tumors can be reduced by preventive vaccination with viral antigens or attenuated live viruses. As mentioned earlier, newly developed HPV vaccines have been effective in decreasing the incidence of HPV-induced premalignant lesions in the cervix.
- In this process, the first step is to provide DCs with tumour-specific antigens. This can be achieved either by culturing ex vivo DCs that have been derived from patients with an adjuvant (that induces DC maturation) and the tumour-specific antigen, and then injecting these cells back into the patient, or by inducing DCs to take up the tumour-specific antigen in vivo. To improve the therapeutic use of DC vaccination strategies it is important to understand the biology of DCs and how they regulate the innate and the adaptive immune systems â particularly in the context of the tumour microenvironment. T
- a | Random targeting of dendritic cells (DCs) in 'endogenous' vaccination results from in vivo antigen release owing to immunogenic cell death in response to chemotherapy, radiotherapy and immunomodulation approaches that are targeted at T cells. b | Vaccines can be based on ex vivo-generated tumour antigen-loaded DCs that are injected back into patients. c | Specific in vivo DC targeting with DC antibodies fused with antigens and with DC activators is shown. d | Targeting DCs in the tumour microenvironment to reprogramme pro-tumour inflammation towards tumour rejection is shown. MHC, major histocompatibility complex; TLR, Toll-like receptor.