Background Flashcards
What are the key functions of the innate immune system?
The innate immune response is nonspecific and provides an initial and rapid (hrs) response to infections by other organisms, but does not provide long-lasting immunity. Its 5 key functions include:
(1) Recruiting immune cells to sites of infection, through the production of factors, including cytokines
(2) Activating the complement cascade
(3) Removing foreign substances present in organs, tissues, blood and lymph, by WBCs
(4) Activating the adaptive immune system through antigen presentation
(5) Providing a physical and chemical barrier to infectious agents
What are the key functions of the adaptive immune system?
The adaptive (acquired) immune response develops more slowly (days) than the innate immune response to an initial exposure but prepares for future immunologic challenges by creating memory to a specific pathogen. It leads to an enhanced response to subsequent encounters with that pathogen. There are 2 types of adaptive immune responses:
(1) Antibody (humoral)—the core function of B lymphocytes which produce antibodies (immunoglobulins)
(2) Cell-mediated—the core function of T lymphocytes
How does the adaptive immune response provide long-lasting protection?
This response is highly adaptable b/c of somatic hypermutation (defined as a process of accelerated somatic mutations), and V(D)J recombination (defined as an irreversible genetic recombination of antigen receptor gene segments). A small number of genes can generate a vast number of different antigen receptors, uniquely expressed on each individual lymphocyte. Since the gene rearrangement leads to an irreversible change in the genetic code, cellular prodigy (memory T cells and memory B cells) inherit the same receptor specificity that confer long-lived specific immunity.
How does cancer evade the immune system?
Cancer cells evade immune surveillance through numerous mechanisms, including:
(1) reduced expression of tumor antigens
(2) downregulation of MHC class I and II molecules thus reducing tumor-antigen presentation
(3) immunosuppressive cytokines such as tumor growth factor-β
(4) induction of immunosuppressive cells (regulatory T cells or myeloid-derived suppressor cells [MDSC])
(5) overexpression of immune checkpoint ligands
Name 4 major types of immunotherapy.
- Checkpoint inhibitors
- Adoptive cell transfer
- Antibody-based therapeutics
- Vaccines
How do checkpoint inhibitors work?
The immune system has checkpoint ligands that protect an organism against an excessive inflammatory response to viral or bacterial infection. Tumors co-opt this mechanism to evade immune cells. For example, tumor cells expressing programmed death ligand-1 (PD-L1) promote T-cell exhaustion, where T cells proliferate slowly and do not function effectively. Cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) expression on tumors can upregulate regulatory T cells which inhibit effector T cells. There are many distinct checkpoint pathways and thus many inhibitors that can be rationally combined.
What type of cancers are most successfully treated with checkpoint inhibitor immunotherapy?
Cancers with a high mutational burden (concept of “altered self”) appear more likely to respond to checkpoint inhibitors. In particular, tumors are more likely to respond if they have neoantigens with high recognition potential, which describes the likelihood that a neoantigen will be presented by MHC molecules and subsequently recognized by T cells.
What are the side effects of checkpoint inhibitors and how are they managed?
Checkpoint inhibitors can cause side effects that appear similar to autoimmune Dz such as skin rash, pneumonitis, colitis, rheumatoid arthritis–like Sx (joint pain, muscle pain), hypophysitis (inflammation of the pituitary) and thyroiditis. These Sx can often be controlled with steroids.
Is dual agent checkpoint inhibition more effective than single agent?
Different classes of checkpoint inhibitors are potentially complementary. Preliminary studies in melanoma and non–small cell lung cancer pts show improved response rates but also increased toxicity with combination PD-1 and CTLA-4 inhibition. CheckMate 067 was a 3-arm trial that randomized Tx-naïve melanoma pts to nivolumab (nivo, PD-1 inhibitor) plus ipilimumab (ipi, CTLA-4 inhibitor) f/b nivo vs. nivo alone vs. ipi alone. 3-yr OS was 58%, 52%, and 34% in combo, nivo alone and ipi alone groups. The overall HR was significantly better in the combo compared to both single agents. But, Tx-related G3–4 AEs occurred in 59% with combo, compared to 21% and 28% with nivo alone and ipi alone. (Wolchok JD et al., NEJM 2017)
How does adoptive cell transfer work?
Adoptive cell transfer involves removing immune cells from the pt, potentially altering them to target a given cancer, growing them ex vivo and then re-infusing them. There are 3 main sources of tumor-specific immune cells: tumor-infiltrating lymphocytes found in surgical tumor specimens which can be cultured, antigen-specific immune cells that are created through repeated exposure to the antigen of interest or antigen-specific T cells that can be created artificially using genetic engineering.
What is CAR T-cell therapy?
Chimeric antigen receptor (CAR) T-cell therapy is a type of adoptive cell transfer therapy where T cells are engineered to target tumor antigens expressed on the membrane of cancer cells. CARs are hybrid (i.e., chimeric) receptors formed by the fusion of 3 parts: an extracellular tumor-specific antibody, a transmembrane portion and an intracellular portion that stimulates T-cell activity when the antigen binds the extracellular antibody. CAR T-cell therapy is not dependent on MHC neoantigen presentation and thus can be effective when MHC molecules have been downregulated by a tumor.
Describe the ELIANA trial which resulted in the 1st FDA approval of a CAR T-cell therapy.
ELIANA included pediatric and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (ALL). CAR T cells were engineered to react to CD19, a protein that is common on B cells. 83% of pts achieved a CR or CR with incomplete blood count recovery within 3 mos of infusion. In the study, 49% of pts experienced grade 3–4 cytokine release syndrome. Within 8 wks of Tx, 18% of pts experienced grade 3–4 neurologic events. (Kymriah [tisagenlecleucel] Prescribing information, Novartis, August 2017)
How does sipuleucel-T works?
Sipuleucel-T refers to an adoptive cell transfer therapy for prostate cancer where a pt’s dendritic cells are extracted and incubated with a protein that contains antigen prostatic acid phosphatase (PAP) which helps the dendritic cells mature. The activated cells are then re-infused into the pt. A complete Tx includes 3 infusions at 2-wk intervals.
What evidence supports the benefit of sipuleucel-T?
The IMPACT trial compared sipuleucel-T to standard of care in men with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer. Sipuleucel-T improved median OS (25.8 vs. 21.7 mo) and 3-yr OS (31.7% vs. 23.0%). (Kantoff PW et al., NEJM 2010)
What is the abscopal effect?
The abscopal effect refers to the ability of a local therapy (e.g., RT, radiofrequency ablation) delivered to 1 or more sites to generate an immune response at distant sites of Dz. Preclinical and clinical studies suggest local RT damages DNA within tumor cells leading to tumor-cell apoptosis/necrosis and tumor-antigen release. These tumor antigens induce antitumor-specific immune responses systemically using similar pathways by which viral/bacterial antigens cause systemic immunity. Abscopal responses d/t RT alone are very rare but appear more common in the setting of checkpoint inhibitors.
