Immune Response Against Tumors, Cancer, Antigens and Immunotherapy Flashcards
Cancer
- Cancer represents uncontrolled growth of transformed cells of the organism.
- Cancer presents a challenge for the immune system as cancer arises from our normal cells to which our immune system is tolerant, but the transformation process potentially produces new determinants that may be immunogenic.
Immungenic Tumors
- Immunogenic tumors are (should be) rejected due to expression of antigens that are recognized by the immune system.
- Tumors are (should be) “seen” by T cells (both CD4+ and CD8+) using TCRs in the same fashion as T cells “see” antigen presented by APCs.
Types of Tumor Antigens
- Tumor-specific antigens (TSA)
- Tumorassociated antigens (TAA)
Tumor-Specific Antigens - expressed UNIQUELY in tumor cells
- Viral proteins (e.g., env, gag, EBNA 3)
- Translocations or point mutations
– BCR: ABL translocation encodes new peptides that the immune system has not been tolerized against.
-Activating mutations in Ras, or inactivating mutations in p53 are examples of point mutations.
- UV induced tumors, leading to mutations in normal host proteins (e.g., HSPgp96 -UV sarcoma)
- Chemically induced tumors (e.g., Heat shock proteins-Hsp70, Hsp90, gp 96)
Tumor-Associated Ags - Normal host proteins expressed in the wrong place
• Cancer/testis antigen (CT Ags)
-These proteins are normally expressed only in testis and not expressed on normal somatic cells including melanocytes; however, cancer cells of different types (breast, lung, ovarian, etc.) overexpress these proteins and can serve as targets for immune attack.
•Prostate specific antigen (PSA)
- increased plasma levels in prostatic adenocarcinoma.
- Modestly elevated in patients with benign prostatic hypertrophy.
•Mucins (MUC1, MUC4)
- associated with breast, colon and pancreatic cancers.
- Normal and malignant epithelial cells produce mucin. In cancer, due to under-glycosylation, the cryptic epitopes in the protein core are exposed and recognized by cytotoxic T lymphocytes.
•HER-2/neu
- transmembrane protein that is related to platelet-derived growth factor (PDGF) receptor.
- Over-expressed in 20% of human breast cancers and is associated with aggressive disease
•Oncofetal Ag: present during embryonic/fetal life, then diminish and reappear in malignancies
- Carcinoembryonic antigen (CEA), a glycoprotein found in alimentary tract, pancreas, liver between 2-6 months of gestation, present at low levels in colon, lung and breast cancers. Not useful for detecting early cancer but blood levels can be used to monitor the efficacy of therapy.
- Alpha fetoprotein (AFP) - produced primarily by fetal liver and yolk sac, exists in small quantities in normal adult serum. Elevated in some patients with liver cancer and non-malignant liver disease (cirrhosis).
However, despite the presence of immunologically recognized antigens in many instances the cellular immune system cannot defeat the cancer due to one or more of the following factors:
- Insufficient numbers and/or decreased avidity of the anti-tumor T cells due to selftolerization mechanisms, i.e., the frequency of tumor antigen-specific T cells is too low to be clinically effective.
- *Tumor cells can be ineffective antigen-presenting cells, due to lack of proper cytokines and/or secondary signals (such as absence of B7 which may induce anergy).
- Poor T cell trafficking to tumor site due to lack of sufficient vasculature
- *Active suppression of immune response by regulatory/suppressor lymphocytes (Treg cells) or suppressor myeloid populations
- *Down-regulation of MHC and peptide processing molecules that can “hide” tumors from CTL recognition and lysis.
- *Tumors can secrete suppressive cytokines such as TGFb which stimulates accumulation of T regulatory cells (Treg) and dampens the immune response.
- *T cell exhaustion due to the actions of CTLA-4 and PD-1 molecules.
Strategies to increase the effectiveness of cancer immunotherapy:
- *Lymphodepletion of regulatory (suppressor) T cells accompanied by adoptive transfer of cytotoxic T lymphocytes (by radiation or drugs such as Cytoxan)
- *Lymphodepletion to create a partially lymphopenic environment, creating “space” for expansion of anti-tumor T cells
- Patient-specific therapy as practiced in CAR-T therapy
Four General Strategies for more effective cancer immunotherapy:
- Cancer vaccines – to generate/augment anti-tumor response:
- Innate/nonspecific immunity – e.g., via BCG, C. parvum, cytokines (IL-2, IFN-I) injections
- Adaptive immunity – e.g., via tumor peptide, protein, RNA, DNA, tumor lysate, tumor extract (heat-shock proteins), or “loaded” DC injections
- Results have been marginal and mixed for both approaches
- Remove immune suppression and enhance anti-tumor immune response (e.g., Treg depletion, CTLA-4 blockade alone, or in conjunction with cancer vaccines or with blockade of other checkpoint inhibitory receptors such as PD-L1, etc.). Objective results quite promising!
- Adoptive cellular therapies –e.g., LAK (lymphokine-activated killer) cells, peptide-expanded or non-specifically stimulated anti-tumor T cells, and CAR-T with excellent outcomes
- Antibody-based anti-cancer therapies - the use of monoclonal Ab against cancer cell surface markers is extremely effective in some cancers.
Non-Specific Cancer Immunotherapy - Cytokines
- Interleukin-2 nonspecifically stimulates proliferation and activation of T cells and NK cells. Effective in treatment of melanoma and renal cancer (~10% objective clinical responses).
- Type I Interferons such as Interferon-alpha has been extensively used in clinical trials. Effective in treatment of numerous cancers including hairy cell leukemia, chronic myelogenous leukemia, lymphomas, AIDS-associated Kaposi’s sarcoma, and melanoma. Likely operates by killing tumor cells (particularly myeloid) directly as well as providing and/or inducing signals 2/3 (i.e., IL-12 &18 for IFN-I)
Non-Specific Cancer Immunotherapy - Bacteria and Bacterial Products
- BCG (Baceille-Calmette-Guerin)
- Intravesicular instillation of BCG is effective in treatment of superficial bladder cancer.
- Also used as an adjuvant to boost the effectiveness of cancer vaccines
- Microbial products
• Developed to avoid risks associated with use of intact organisms. Cell wall skeleton of BCG, Lipid A, and Monophosphoryl lipid A (MPL) have been used.
*Both work via binding to TLRs and other innate sensors to boost immunity and/or inflammatory response
*(Mechanisms poorly understood)
Tumor Specific Vaccines
•Target viral proteins - If oncogenic viruses are involved in tumorigenesis, vaccination against the virus will also be an effective anti-cancer measure.
- Ceravix and Gardasil vaccines for papilloma virus and cervical cancer
- HBV vaccine and hepatocellular carcinoma.
- Peptide antigen vaccines: mutated Ras, mutated p53, Her2/neu, MART-1, gp100, MUC1, and CEA antigens are being used to vaccinate cancer patients.
- Dendritic cells pulsed with peptides/tumor lysates, DC-tumor cell hybrid vaccines (numerous clinical trials) -Sipuleucel-T for prostate cancer.
*To date, no cytokine, non-specific or tumor vaccine has displayed significant clinical efficacy, other than the HPV vaccine vs. cervical cancer.
Immunomodulation of Immune Suppression
- A recent development in the field of cancer immunotherapy is the use of checkpoint blockades. That is, using antibodies to release the negative regulators of immune activation (the immune checkpoints).
- This goal has been accomplished by using mAbs directed against CTLA-4 and the PD-1 pathway, alone or in combination. [NOBEL PRIZE 2018!!!]
*Remember that CTLA-4 interacts with CD80/CD86 to inhibit CD28-mediated T cell activation. Antibodies against CTLA-4 prevent this inhibition. PD-1 is the programmed cell death receptor that interacts with PD-L1 to trigger apoptosis in T cells. Antibodies against either PD-1 or PD- L1 can prevent this event from occurring.
Immunomodulation of Immune Suppression - Keytruda
- Immune Checkpoint Blockade
- There are currently multiple FDA-approved antibodies for this application; Keytruda was the first one approved.
Immunomodulation of Immune Suppression - Cancers that respond
•Cancers that respond very well (40- 50% of the time) to checkpoint blockade include:
-Hodgkin’s disease and melanoma
•Cancers with an intermediate response (15-25% efficacy) include:
-NSCLC, head and neck cancers, bladder and urinary tract cancers, renal cell carcinoma and liver cancer.
•All other types of cancers display a low or negative response to checkpoint blockade therapy.
Immunomodulation of Immune Suppression - The Bad News
- Unfortunately, 60-65% of patients exhibit immune related adverse events (AEs) affecting skin, GI tract and endocrine organs. Occasionally, autoimmune disease develops confirming the role of CTLA-4 in the maintenance of self-tolerance. These AEs include enteropathy, autoimmune cytopenias, hemolytic anemia, thyroid disease, arthritis, psoriasis, granulomatous lung disease and lymphocytic infiltration of non-immune organs.
- Interestingly, and for reasons not completely understood, the commensal microbiome composition of the patient influences the efficacy of anti-PD-1 therapy, as well as anti-CTLA-4 treatment. Cancer itself or the concomitant use of antibiotics may result in microbiome dysbiosis. It appears that certain bacterial strains influence IL-12 production by the innate immune system and migration of T cells into the tumor, both of which will affect therapeutic efficacy.
- In addition, patient HLA genotype influences success, in that patients that are homogenous at one or more class I loci do significantly worse in terms of outcome.
- Overall, the fact that checkpoint blockade therapy does indeed enable anti-cancer immune responses in many patients indicates that in many individuals their immune system is capable of recognizing either tumor-specific or self-antigens.
Other Kinds of Antibody-Based Therapy - Mechanisms
- Agonist action causes direct death of cell
- Antagonist prevents signaling, proliferation
- Payload delivery of an enzyme or toxin
Adoptive Cellular Therapy (ACT) - Chimeric antigen-receptor modified T cells (CAR-T) are made of…
- The CARs are generally composed on one or more intracellular T cell signaling domains (e.g., CD3-zeta with CD28, 4-1BB, ICOS or OX-40) and an extracellular antigen-binding domain derived from an antibody (scFv).
- Such a construct generally has a higher affinity than the native TCR and is no longer HLA-restricted in its recognition processes.
