II. Definitions
- Cancer Immunotherapy
- Blocks cancer cell proliferation by interfering with specific tumor-related molecules
- Contrast with traditional cytotoxic Chemotherapy which non-specifically targets dividing cells
III. Indications
- Metastatic or advanced cancer with specific primary cancers and Tumor Markers
- As of 2012 qualifying patients represented only 8% of the 610,000 advanced cancer patients in U.S.
- Efficacy varies widely by tumor type, marker type and agent
- Marquart (2018) JAMA Oncol 4(8):1093-8 [PubMed]
IV. Background
- Cancer Immunotherapy targets specifc tumor related markers on cells based on Genetic Testing
- Imatinib (Gleevec) was the prototype agent first used for Chronic Myeloid Leukemia (targets Tyrosine Kinase)
- Future of Chemotherapy may in part be in directed targeted marker-based therapies
- Tumors may be treated more by Tumor Marker than by region or cancer type
V. Types
-
Monoclonal Antibody-Mediated Chemotherapy
- Example: Rituximab (Rituxan), used in Non-Hodgkin's Lymphoma and Rheumatoid Arthritis
- Monoclonal antibodies act at targeted cells via oncogene downregulation or tumor cell flagging for destruction
- Initially targeted to CD20 on immune cells to treat Lymphoma and Leukemia, later for Autoimmune Disease
- Targeted to solid tumors (e.g. Breast Cancer, Lung Cancer, Colon Cancer) , binding extracellular Ligands and receptors
- xHER2 (e.g. Trastuzumab) have been very effective in HER2 positive Breast Cancer
- xEGFR (e.g. Cetuximab) have been effective in metastatic Colorectal Cancer (without RAS mutation)
-
Small Molecule Inhibitor-Mediated Chemotherapy
- Example: Imatinib (Gleevec)
- Primarily oral agents (contrast with other Chemotherapy which is primarily intravenous)
- Targeted to Protein kinases (esp. Tyrosine Kinase), interfering with EGFR, HER2-neu and VEGF
- Small molecules that principally act intracellularly, with less Specificity than monoclonal antibodies
- Small molecules also effect healthy tissue, and therefore have systemic effects
- Widely variable efficacy depending on tumor type
-
Antibody-Drug Conjugates (ADC)
- Example: Trastuzumab emtansine (T-DM1, trade name: Kadcyla) for refractory, advanced HER2+ Breast Cancer
- Monoclonal Antibody bound to cytotoxic Chemotherapy is specifically directed at tumor cells
- Local destruction of normal cells in vicinity of tageted tumor cells
- Systemic effects include Fatigue, Nausea, Peripheral Neuropathy and Thrombocytopenia
- Active Immunotherapy (tumor cell specific targeting)
- Monoclonal Antibody-Mediated Chemotherapy
- CAR T-Cell Therapy
- Oncologic Vaccines (e.g. sipuleucel-T, Prostate Cancer)
- Passive Immunotherapy (Immuno-modulators)
- Cytokines
- Immune Checkpoint Inhibitors
- Counter tumor cell generated Immune Suppression by blocking their activity on T-Cells
- Immune Checkpoint Inhibitors are very effective in mestatatic Non-Small Cell Lung Cancer
- Example: Pembrolizumab (Keytruda) targets Programmed Cell Death Protein 1 (PD-1)
- Example: Atezolizumab (Tecentriq) targets Programmed Death Ligand-1 (PDL-1)
- Example: Ipilimumab (Yervoy) targets Cytotoxic T Lymphocyte Associated-4 (CTLA-4)
VI. Adverse Effects
- Adverse Effects varies by type of targeted Chemotherapy
- Bankruptcy ("Financial Toxicity")
- Regimens are very expensive, and in some cases without efficacy to justify their use
- Cancer patients often modify or fail to fill their cancer Chemotherapy prescriptions due to cost
- Zafar (2013) Oncologist 18(4):381-90 [PubMed]
- Ramsey (2016) J Clin Oncol 34(9): 980-6 [PubMed]
- Head and Neck
- Pituitary inflammation (hypophysitis)
- Occurs with CTLA-4 inhibitors and PD-L1 inhibitors
- Dry Mouth
- Pituitary inflammation (hypophysitis)
- Endocrine
- Hypothyroidism
- Adrenal Insufficiency
- Diabetes Mellitus (autoimmune)
-
Lung
- Pneumonitis
-
Abdomen
- Hepatitis
- Pancreatitis
- Enterocolitis
- Musculoskeletal
- Skin
- Rash
- Vitiligo