Cancer Flashcards
What is cancer?
- An uncontrolled overgrowth of highly abnormal cells which infiltrate and destroy healthy tissue
- They are formed from our own cells, not foreign, so this is not why they are immunogenic
- Can form solid masses (tumours) or be suspended in the blood (leukemia)
- Can spread around the body (metastasis)
- Caused by mutations in oncogenes and tumour suppressor genes
- Genetically unstable= gives cancer the opportunity to evolve under a selective pressure
What is the scale of the cancer epidemic?
- Affects 1/3rd to ½ people in their lifetime
- ¼ to 1/3rd of those afflicted die
- Incidence rates are still climbing for many cancers, but mortality rates are falling due to earlier detection and breakthroughs in the therapy
What are the 3 ways that the immune system protects the body from cancer?
- Eradicates viruses (eg, HPV, EBV, HHV8, HTLV-1) that cause cancer → about 5% cancer caused by HPV
- Rapid elimination of pathogens and resolution of inflammation → inflammation is a risk factor for cancer – cancer typically occurs in the presence of chronic inflammation, eg) liver cirrhosis, colitis….
- Specific identified and eliminates cancer cells → immunosurveillance
What are the 4 things that can make a tumour immunogenic?
• DAMPs → tumours tend to have areas of necrosis within them, so release DAMPs. This stimulates macrophages and neutrophils to enter the tumour. Some of these are directly tumoricidial – could phagocytose cells, or secrete cytokines etc…
− HMGB1
− HSP
− IL-1a
• Stress related ligands → Transformed cells (with mutations) upregulate stress related atnigens that bind to innate immune receptors.
− MICA/B, RAET1 → NKG2D (stimulates NK cells)
− CD112/CD115 → DMAM
• Tumour associated antigens (TAA) →
− Over-expressed tissue-specific proteins/differentiation antigens eg) MART1/Melan-A → unsure as to why this becomes immunogenic, as still self and should have been selected against
− Cancter testist antigens (eg, MAGE1, LAGE1) → typically expressed in sperm, but for some reason become expressed in cancer cells. Immune system recognizes them because they are normally expressed in the testis (an immune privileged site), so haven’t been seen and selected against.
• Tumour specific antigens (TSA) →
− Viral proteins (cancer causing viruses)
− Neoantigens (oncoproteins and passenger proteins)
What is the immunosurveillance hypothesis?
- Beginning of 20th century, Paul Ehrlick theorises that cancer cells appear continuously throughout life, but are mostly destroyed before they become a problem by immune cells
- In the 1950s, following the demonstration of TSAs, Thomas & Macfarlane Burnet reassert this theorem by adding that neoantigens created by mutations would allow the immune system to recognise cancer cells.
What was the experimental evidence for the immunosurveillance hypothesis?
Shankaran et al, 2001: IFNy and lymphocytes prevent primary tumour development:
• RAG2 deficient mice (lacking B and T cells) develop more sarcomas in response to MCA carcinogen when compared with immunocompetent mice
• They also developed more spontaneous neoplasms upon ageing
• Similar results were also found in IFNy receptor KO, STAT1 KO
Immune recognition was thought to be mediated by T cells:
• Mediated by T cells recognizing neoantigens
• Demonstrated experimentally using an MCA induced tumour
− They either directly generated escape tumours (progresses that have escaped immunosurveillance) and transplanted these into WT mice, or they just cloned it to create sub-clones of the original cell line, some that would progress and others that would not
− They wanted to compare gene expression in clones that regress compared to those that progress
− Discovered that all regressors (clones that would shrink upon injection into a mouse) had a neoantigen in spectrin B2
− This protein is actually nothing to do with cancer- is a passenger protein, not involved in driving cancer
− It was found that lymphocytes from a mouse that is harbouring a regressor clone would secrete IFNy only upon injection with the spectrin B2 neoantigen.
− When they took a progressor clone and forced it to express the spectrin B2 neoepitope, it converted into a regressor clone
However, increasing evidence shows involvement of innate immunity too:
What other evidence (using models) showed a role for both innate and adaptive immunity in cancer immunosurveillance?
Carcinogen induced tumours:
Cells of the innate and apative immune system are critical for their elimination:
• RAG -/- (lack B and T cells) → increased MCA induced sarcomas
• SCID (lack T, B and NK cells) → increased MCA induced sarcomas
• TCR -/- (lack T cells) → increased DMBA induced skin tumours
• CD11 -/- (lacks eosinophils) → increased MCA induced sarcomas
• IFN -/- → increased MCA and DMBA induced tumours
IFNs can contribute in a number of ways:
• Enhance MHC-I expression, making them better targets for CD8+ T cells
• IFNy signaling in host immune cells and stromal cells plays an important role
• Contributes to an inflammatory foreign body reaction that encapsulates injected MCA, limiting its spread and reducing carcinogenic effects.
Initiation of sarcomas requires an inflammatory event:
• Induction of DMBA skin carcinomas is MyD88, TNFa, RAGE and IDO dependent
Not all immune cells function equally:
• yd T cells and CD8+ T cells confer protection from DMBA induced papillomoas
• In contrast, CD4+ T cells promote tumour progression, implying opposite roles for ab T cell subsets in the protection or promotion of DMBA induced carcinogenesis
• One mechanism by with yd T cells and CD8+ T cells might regulate tumour development is through recognition by NKG2D of the stress ligand RAE1 that is induced in the skin after DMBA treatment.
Spontaneous Tumours in Immunodeficient Mice
• An elegant approach to examining the role of the immune system in controlling tumour development is to simply remove specific components of the murine immune system and monitor the mice as they age for the development of spontaneous tumours.
• Mice have long telomeres and normally have low incident of spontaneous tumour development}
• RAG -/- → mice develop intestinal and lung neoplasms
• IFNy -/- → mice develop disseminated lymphomas and lung adenocarcinomas
• Pfp -/- → mice develop B cell lymphomas - very striking penetrance of B cell lymphomas – increases from 0-5% in WT mice to 40-60%.
− When mice additionally lack B2 microglobulin or IFNy, there is an even greater prevalence, with an earlier onset.
− The absence of other lymphocyte cytotoxic pathways such as TRAIL or FasL also increases the susceptibility of mice to spontaneous lymphomas.
− Interestingly, human patients with perforin mutations that develop familial haemophagocytic lymphohistiocytosis also develop leukemia and lymphomas.
→ Provides strong evidence that cytotoxic molecule is in lymphocytes protect the host from spontaneous tumour development.
Genetic Tumour Models and Immundeficiency
p53 is the key tumour suppressor. Mice with p53 mutations are genetically predisposed to tumour development:
• IFNyR -/- Trp53 -/- (insensitive to IFNy and lacks p53) → mice develop broader spectrum of tumours with earlier onset than solely Trp53 mice
• Prp -/- Trp53 +/- (lacks perforin and is heterozygous for p53) → mice develop B cell lymphomas with earlier onset than Trp53 +/- mice
→ Provides evidence that immune components participate in the elimination of nascent transformed cells
What is the idea of immune sculpting, and how did it chance the original view of cancer immunosurveillance?
Shankaran et al, 2001:
• 40% of MCA sarcomas derived from immunodeficient mice were spontaneously rejected when transplanted into WT mice, whereas all MCA sarcomas from WT mice grew progressively when transplanted into WT mice
• Thus, tumours formed in the absence of an intact immune system are, as a group, more immunogenic than tumours from immunocompetent hosts
• Those that form in an intact immune system have been immunoedited → their immunogenicity has been wiped.
− By eliinating tumor cells of high intrinsic immunogenicity, this imprinting process may select for tumor cell variants of reduced immunogenicity and therefore favor the generation of tumors that are either poorly recognized by the immune system or that have acquired mechanisms that suppress immune effector functions.
− In this manner, the immunologic sculpting of developing tumor cells provides them with mechanisms to resist the extrinsic tumor-suppressor actions of the immune system
• Based on the studies summarized in this review, the term “cancer immunosurveillance” no longer suffices to accurately describe the complex interactions that occur between a developing tumor and the immune system of the host.
• As originally conceived, cancer immunosurveillance was thought to be a host-protective function carried out by the adaptive immune system only at the earliest stages of cellular transformation.
• In contrast, we now recognize that both the innate and adaptive immune compartments participate in the process and serve not only to protect the host from tumour development but also to sculpt, or edit, the immunogenicity of tumors that may eventually form.
• Therefore, we have proposed the use of the broader term “cancer immunoediting” to more appropriately emphasize the dual roles of immunity in not only preventing but also shaping neoplastic disease
We now view cancer immunoediting this as a dynamic process of 3 distinct phases:
• Elimination
• Equilibrium
• Escape
What is the new definition of the Elimination phase?
The elimination phase is a modernized view of cancer immunosurveillance in which molecules and cells of innate and adaptive immunity work together to detect the presence of a developing tumour, and destroy it before it becomes clinically apparent.
Describe the hypothesis of the equilibrium phase (immune mediated tumour dormancy).
• Historically, tumour dormancy was used to describe latent tumours present in patients for decades that may eventually recur as local lesions or form distant metastases → it explains the long latency period from the initial transformation event to the escape phase and emergence of malignant disease
• It is the longest immunoediting phase – could be 20 years between exposure to a carcinogen and development of malignancy
• Tumours in the equilibrium phase are specifically controlled by components of the immune system
• The host immune system and tumour cells enter a dynamic balance, where anti-tumour immunity contains but does not fully eradicate tumour cells, some of which have acquired means of evading immune-mediated recognition.
• Immunoediting (the destruction of more immunogenic cells) leaves behind less immunogenic cells, that can avoid immune recognition and stay dormant.
• We envision this period to be a crucible of Darwinian selection: Although many of the original tumor cell escape variants are destroyed, new variants arise carrying different mutations that provide them with increased resistance to immune attack.
− It has been proposed that the “mutator phenotype” of tumor cells (157) may result from the three types of genetic instability observed in cancer: nucleotide-excision repair instability (NIN), microsatellite instability (MIN), and chromosomal instability (CIN).
Describe the experimental evidence presented by Koebel et al for the equilibrium phase.
- Using a low-dose regimen of the carcinogen MCA, we reported the first experimental demonstration that immunity maintains primary occult cancer lesions in an equilibrium state
- Treatment of naive wild-type mice with low doses of MCA led to overt tumors in only a low proportion of mice.
- When the remaining carcinogen-treated mice were rendered immunodeficient via depletion of CD4+ and CD8+ T cells and/or neutralization of IFN-γ, sarcomas rapidly grew out at the original carcinogen injection site in approximately 50% of the group → so adaptive immunity is keeping the tumours in check.
- In contrast, mAbs that deplete NK cells failed to cause the emergence of progressively growing tumors
- These results support the conclusion that adaptive immunity, but not innate immunity, is responsible for maintaining the equilibrium phase. They also help to mechanistically distinguish this phase from elimination, where both innate and adaptive immunity are required.
- Tumours controlled by immunity displayed fewer Ki67+ atypical fibroblasts and more terminal deoxynucleotidyl transferase dUTP end nick labeling (TUNEL) staining cells than progressively growing sarcomas.
- So dormant masses have reduced proliferation, increased apoptosis and marked T cell infiltration → supportive of an active immune response against them
- Occult tumors arising after immunodepletion were, on the whole, highly immunogenic, with 40% of the cell lines being rejected after transplantation into wild-type mice.
- In contrast, the rare spontaneous tumors that grew out of mice treated with control mAbs were poorly immunogenic and grew progressively when transplanted into wild-type recipients → mutator phenotype
- Thus, tumor cells that can stay in equilibrium by adaptive immunity remain highly immunogenic and displayed an unedited phenotype, as they formed progressors when immunodepleted, whereas dormant sarcoma cells that spontaneously escaped immune control to become actively growing tumors displayed reduced immunogenicity, indicating that they had undergone editing
• Recently, additional studies using different mouse models of cancer corroborated our findings for the existence of the equilibrium phase by additionally demonstrating that immunity can control primary carcinomas and metastases for extended periods of time.
− One study demonstrates that immunity can prevent the outgrowth of micrometastases for an extended period of time in an oncogenedriven model of melanoma → Depletion of CD8+ T cells in RET AAD mice (uveal melanoma) significantly accelerated the outgrowth of metastatic lesions to visceral organs, indicating that immunity is one significant barrier disseminated tumor cells must overcome to establish metastatic disease.
− CD4, but expecially CD8, depletion allows progression of lymphoma
− Mouse B-cell lymphoma (BCL1) dormancy is induced by prior immunization with BCL1-derived Ig
Describe the evidence showing Th1 cytokines are required for tumour dormancy.
- Using a pancreatic neuroendocrine tumour model (RIP1-Tag2), adoptive transfer of Tag-specific CD4+ T cells induces dormancy through inhibiting angiogenesis
- Is independent of CD8+ T cells – there is no marked infiltration of tumours by these
- Requires both IFNy and TNFR signaling
- The absence of either accelerates tumour progression
- Was later shown in 2013 that IFNy and TNF together induce senescence (permanent cell cycle arrest) in cancer cel;s through induction of p16INK4A.
Describe the theory of the escape phase.
- When transformed cells acquire adaptations allowing them to grow unhindered by the immune system
- Represents the failure of the immune system to eliminate or control transformed cells, allowing surviving tumour cells to grow in an immunologically unrestricted manner.
- Cancer cells undergo stochastic genetic and epigenetic changes generating the modifications necessary to circumvent immunological defenses.
So,
• As a result of the Darwinian selection on mutated tumours and immunediting (where destruction of more immunogenic cells eaves behind less immunogenic cells, that can avoid immune recognition) the end result of the equilibrium process is a new population of tumor clones with reduced immunogenicity,
• In the escape phase, tumor cell variants selected in the equilibrium phase now can grow in an immunologically intact environment
Causes for loss of control can be grouped:
• Reduced immune recognition
• Resistance to cytotoxic effects of immunity
• Immunosuppressive tumour microenvironment
How do tumours escape immune destruction in the escape phase?
Tumour Cell Modifications to Evade Immune Detection
Either due to lack of immunological recognition, or induction of central tolerance:
• Central tolerance → self reactive T cells eliminated or converted to regulatory phenotype in the thymus
− In this case, in the absence of neoantigen expression, tumours may remain invisible to the adaptive immune system
In addition, tumour cells can acquire other features that facilitate evasion:
• Reduced tumour associated antigens (as mentioned above, this will ensure cells remain tolerised)
• Loss of antigen processing (TAP1, LMP2, LMP7)
• Decreased MHC-I
• Downregulate stress signals, eg) MICA/B → results in a loss of a ligand for the NK effector molecule NKG2D
• Suppression of pro-inflammatory cytokine production
Resistance to Cytotoxic Effects of Immunity
• Even when TAAs are expressed, tumours can evade effector lymphocytes by upregulating expression of anti-apoptotic molecules BCL-xL and FLIP
• Resistance to Lysis by immune cells can be acquired through expression of mutated inactive death recetors, including Fas
Generating an Immunosuppressive Microenvironment
• Increasing PD-L1 and HLA-E on the cell surface dampens the cytotoxic action of T cells or induces T cell apoptosis
• Increasing chronic inflammation (GM-CSF, IL-1B, TNFa, PGE2, IL-4) → reduced cell-mediated immunity
• Increasing anti-inflammtory cytokines (both by the tumour and other cells in the microenvironment):
− TGFB → inhibits DCs, T cells and NK function, induces Tregs
− VEGF → criticial for angiogenesis
− IL-10 →
− M2 macrophages → inhibit anti-tumour immunity through production of TGFB and IL-10, and can promote angiogenesis
− MDSCs → inhibit lymphocyte function
− Tregs → inhibit CTL function though TGFB, IL-2 mop up, granzyme and CTLA-4
• Increased IDO → inhibits CD8+ proliferation and promotes CD4+ apoptosis
• Increases iNOS
What are the 8 pieces of clinical evidence for the immunoediting hypothesis in humans?
• Delay in cancer occurrence and recurrence
− A plethora of evidence suggests cancers can lie dormant in patients for as much as 20 years before malignant disease progresses to detectable levels
− 20-40% of patients with breast or prostate cancer will relapse years or decades later
− Circulating disseminated cancer cells can exist for years after treatment without reestablishment of disease (minimal residual disease)
• Paraneoplastic disease
− In patients with PND, spontaneous immune responses against malignant cells have been demonstrated caused by cross-reactivity between the anti-tumour immune response and neurologic antigens
− Tumour specific T cells have also been found in patients with PND
• Increased cancer risk for patients with acquired immunodeficiency
− Most severely immunodeficient patients succumb to infection, so not as easy to model as in rodents however
− Patients with AIDs have increased frequency of malignancies
− Most often, these malignancies are associated with viruses and initiated by viral oncogenes, eg) lymphomas with EBV, Kaposi’s sarcoma with HSV and cervical cancer with HPV
− However, as well as virally-induced tumours, there is evidence of increased incidence of cancer such as lung adenocarcinoma
− 3 out of 8 cancer patients experienced cancer relapse following immunosuppression 10 years after ‘remission’, whereas those that hadn’t undergone immunosuppression only had a 2% relapse rate
• Spontaneous remission
− Screening cancer cell lines with autologous patient serum identified spontaneous antibody responses to autologous cancers → antibody responses in patient serum have been found fore more than 100 TAAs
− Among the shared antibody responses were those against cancer testis antigens and mutant p53
− The phenomenon of spontaneously regressing melanoma lesions accompanied by clonal expansion of T cells is arguable the strongest evidence for the elimination phase – it is found in the absence of immunotherapy
• Tumour infiltrating lymphocytes are prognostic indicators – the immunoscore
− Tumour infiltration with T cells, NK cells have been associated with an improved prognosis for a number of different tumour types
− First observed in melanoma – where patients with high levels of CD8+ T cell infiltration survive longer
− In ovarian cancer, 38% of patients with high numbers of TILs surivived more than 5 years compared with 4.5% of patients with low numbers of TILs
− Galon et al. propose that infiltration of tumour by memory CD8+ T cells in CRC is more informative than staging alone.
• Tumous developing from transplanted organs
− Increase in incidence of cancer in immunosuppressed individuals following organ transplantation , eg) patients receiving kidney transplants have a 3-fold increase in the incidence of malignancy
− This results from the unintentional transplantation of cancer cells from organ to donor – the donor who had no previously clinical history of malignancy or was in remission.
• Immunotherapy works
• Immunogenicity of tumour with microsatellite instability
− Tumours with high levels of genetic instability – ie, defects in DNA mismatch repair lead to deletion of microsatellites
− This high rate of mutation generates novel tumour antigens that can be recognised by the immune system
Describe the cancer immunity cycle.
. Release of cancer cell antigens:
• In the first step, neoantigens created by oncogenesis are released and captured by dendritic cells (DCs) for processing. In order for this step to yield an anticancer T cell response, it must be accompanied by danger signals.
• There are two types of cell death (that will ultimately release antigens) – necrosis and apoptosis. Necrosis is conserved to be more immunogenic. You get necrosis after radiotherapy. A lot of targeted cancer therapies work on inducing apoptosis, this is still good because it is cell death, but it is considered to be more tolerogenic cell death. People generally try and avoid necrosis because the patients already feel ill, and necrosis might make them feel works – but it could be better in the long run.
- Cancer antigen presentation:
• DCs present the captured antigens on MHCI and II molecules to T cells.
• Factors such as TNFa, IFNs, CD40 etc… stimulate the DCs to leave the tumour and migrate to the lymph node in order to present the antigens to T cells. IL-10, IL-4 and iL-13 are inhibitory. - Priming and activation of T cells:
• Antigen presentation to T cells in the lymph node results in the priming and activation of effector T cell responses against the cancer specific antigens that are viewed as foreign,.
• The nature of the immune response is determined at this stage, with a critical balance representing the ratio of T effector cells versus T regulatory cells being key to the final outcome
• Factors such as IL-2, IL-12, OX40/OXO40L are stimulatory in this process, and CTLA-4, PDL1/PD1 etc… are inhibitory. - Trafficking of T cells to tumours
• This is coordinated by chemokines, CX3CL1, CXCL9, CXCL10 and CCL5. - Infiltration of T cells into tumours
• Mediated by adhesion molecules such as LFA-1/ICAM-1 and the selectins, inhibited by VEGF. - Recognition of cancer cells by T cells
• Mediated by the TCR, inhibited by reduced MHC expression on cancer cells. - Killing of cancer cells
• Mediated by IFNy and T cell granule content. Inhibited by TGF-B, IDO, PDL1, Arginase etc…
→ Causes more TAAs to be releaed, and the cycle starts again.
What is cancer immunotherapy, and what is its goal?
cancer immunotherapy is ‘treatment to boost or restore the ability of the immune sytem to fight cancer”.
• The goal is to reinitiate a self-sustaining cancer immunity cycle , without generating unrestrained autoimmunity responses
• This is often a limitation of immunotherapy – you are attacking a cell that is a self cell, so there is a dange you could provoke autoimmune reactions (seen in paraneoplastic syndrome).
Describe administraiton of cytokines as cancer immunotherapy (High dose bolus IL-2, IFNa, , GM-CSF, IL-7, IL-15, IL-12, IFNb)
- Stimulate a broad-based immune response
- Pleotropic effects (sometimes opposing) on immune cells – but also direct effects on tumour cells
- Specific anti-tumour activity therefore often unknown
- There are problems with drug delivery – see later
- Can have considerable side effects → fever, fatigue, depression, autoimmunity, hypotension
- Can be used as adjuvants when combined with vaccine therapies
- An important property of cytokine signalling is the degree of redundancy – where multiple cytokines have the same functional effects → can make therapeutics challenging as other cytokines may compensate for changes in another.
Lee & Margolin, 2011:
To date, two cytokines have achieved FDA approval as single agents for cancer treatment:
High-dose, bolus IL-2 for metastatic melanoma:
• Potential of cytokines in cancer immunology is best exemplified by IL-2
• High-dose IL-2-activated peripheral blood mononuclear cells with the phenotype and functional characteristics of activated NK cells,
• Induces objective clinical responses in 15–20% of patients with advanced melanoma and durable complete responses in 5–7% of these patients
• Its highly pleotropic effects as a potent activator of both effector T cells and Tregs is a reason for its low response rates and notorious toxicities
• The toxicity profile of IL-2 is largely associated with a capillary leak syndrome, which is characterized by hypotension, tachycardia and peripheral edema. In addition, IL-2 can cause constitutional symptoms such as fever, chill and fatigue, gastrointestinal side effects such as nausea, vomiting, anorexia.
• There has been intense interest in the discovery of predictive biomarkers for better selection of patients likely to respond to IL-2 therapy for both RCC and melanoma. A defined polymorphism in the CCR5 gene (CCR5Δ32) was associated with decreased survival following IL-2 administration in patients with Stage IV melanoma compared to patients not carrying the deletion.
IFNa for the adjuvant therapy of stage III melanoma:
• Type I IFNs, which include IFN-a and IFN-B have emerged as the most clinically useful IFNs for the treatment of cancer.
• Type I IFNs induce expression of major histocompatibility complex (MHC) class I molecules on tumor cells and activate cytotoxic T lymphocytes (CTLs), natural killer (NK) cells and macrophages
• The Type I IFNs can exert cytostatic and possibly apoptotic effects on tumor cells as well as anti-angiogenic effects on tumor neovasculature
• IFN-a is the only currently approved adjuvant therapy for patients with high-risk Stage II or Stage III melanoma
• IFN-a is also approved for the treatment of AIDS-related Kaposi’s sarcoma, advanced renal cancer, hairy cell leukemia (HCL) and chronic myelogenous leukemia (CML).
• The toxicity profile of IFN-D is usually dose-related, and most side effects can be managed without discontinuation of treatment. Constitutional symptoms including fever, fatigue, headaches, gastrointestinal symptoms and myalgias are quite common and will likely occur in 80% or more of patients.
Other cytokines have entered clinical trials for patients with advanced cancer:
GM-CSF:
• GM-CSF is produced by monocytic cells and T cells and promotes antigen presentation and T cell homeostasis.
• The potential for GM-CSF to stimulate immune responses has been shown in many tumor models, including a murine melanoma in which transgenic expression of GM-CSF provided protection to subsequent tumor challenge in over 90% of the animals
IL-7:
• A potential therapeutic advantage of IL-7 over IL-2 is its selectivity for expanding CD8+ T cell populations over CD4+FOXP3+ regulatory T cells
• In murine models, recombinant IL-7 has been found to augment antigen-specific T cell responses after vaccination and adoptive cell therapy and this is now being evaluated in humans through two clinical trials
• Another important area of investigation is the potential role of IL-7 in promoting T-cell recovery after chemotherapy or hematopoietic stem cell transplantation.
• Early phase clinical trials on patients with advanced malignancy have demonstrated recombinant IL-7 to be well-tolerated with limited toxicity at biologically active doses.
IL-15:
• IL-15 acts to block IL-2-induced apoptosis.
• IL-15 also supports the persistence of memory CD8+ T cells, which may be important for maintaining long-term anti-tumor immunity [101].
• IL-15 has demonstrated significant therapeutic activity in several pre-clinical murine models of cancer [102].
IL-12:
• L-12 is produced mainly by phagocytic cells in response to antigenic stimulation, leading to cytokine production, primarily of IFN-γ, from NK and T cells.
• IL-12 also acts as a growth factor for activated NK and T cells, promotes CD4+ T cell differentiation into Th1 CD4+ T cells and enhances the activity of CD8+CTLs
• IL-12 has demonstrated anti-tumor activity in murine models of melanoma, colon carcinoma, mammary carcinoma and sarcoma
IFNbeta:
• IFN-β is more potent than IFN-a in inducing antiproliferative effects in preclinical cancer models
• In spite of its higher antiproliferative potential compared to IFN-D, the clinical use of IFN-β in cancer therapy has been limited by its low bioavailability and sustained side effects
• This may be overcome by delivery in different routes and schedules.
