Targeted Cancer Therapy

See Also

Definitions

Cancer Immunotherapy
1. Blocks cancer cell proliferation by interfering with specific tumor-related molecules
2. Contrast with traditional cytotoxic Chemotherapy which non-specifically targets dividing cells

Indications

Metastatic or advanced cancer with specific primary cancers and Tumor Markers
1. As of 2012 qualifying patients represented only 8% of the 610,000 advanced cancer patients in U.S.
2. Efficacy varies widely by tumor type, marker type and agent
3. Marquart (2018) JAMA Oncol 4(8):1093-8 [PubMed]

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)
1. See Small Molecule Inhibitor-Mediated Chemotherapy
Future of Chemotherapy may in part be in directed targeted marker-based therapies
1. Tumors may be treated more by Tumor Marker than by region or cancer type

Types

Monoclonal Antibody-Mediated Chemotherapy
1. Example: Rituximab (Rituxan), used in Non-Hodgkin's Lymphoma and Rheumatoid Arthritis
2. Monoclonal antibodies act at targeted cells via oncogene downregulation or tumor cell flagging for destruction
3. Initially targeted to CD20 on immune cells to treat Lymphoma and Leukemia, later for Autoimmune Disease
4. Targeted to solid tumors (e.g. Breast Cancer, Lung Cancer, Colon Cancer) , binding extracellular Ligands and receptors
  1. xHER2 (e.g. Trastuzumab) have been very effective in HER2 positive Breast Cancer
  2. xEGFR (e.g. Cetuximab) have been effective in metastatic Colorectal Cancer (without RAS mutation)
Small Molecule Inhibitor-Mediated Chemotherapy
1. Example: Imatinib (Gleevec)
2. Primarily oral agents (contrast with other Chemotherapy which is primarily intravenous)
3. Targeted to Protein kinases (esp. Tyrosine Kinase), interfering with EGFR, HER2-neu and VEGF
4. Small molecules that principally act intracellularly, with less Specificity than monoclonal antibodies
5. Small molecules also effect healthy tissue, and therefore have systemic effects
6. Widely variable efficacy depending on tumor type
Antibody-Drug Conjugates (ADC)
1. Example: Trastuzumab emtansine (T-DM1, trade name: Kadcyla) for refractory, advanced HER2+ Breast Cancer
2. Monoclonal Antibody bound to cytotoxic Chemotherapy is specifically directed at tumor cells
3. Local destruction of normal cells in vicinity of tageted tumor cells
4. Systemic effects include Fatigue, Nausea, Peripheral Neuropathy and Thrombocytopenia
Active Immunotherapy (tumor cell specific targeting)
1. Monoclonal Antibody-Mediated Chemotherapy
2. CAR T-Cell Therapy
3. Oncologic Vaccines (e.g. sipuleucel-T, Prostate Cancer)
Passive Immunotherapy (Immuno-modulators)
1. Cytokines
2. Immune Checkpoint Inhibitors
  1. Counter tumor cell generated Immune Suppression by blocking their activity on T-Cells
  2. Immune Checkpoint Inhibitors are very effective in mestatatic Non-Small Cell Lung Cancer
  3. Example: Pembrolizumab (Keytruda) targets Programmed Cell Death Protein 1 (PD-1)
  4. Example: Atezolizumab (Tecentriq) targets Programmed Death Ligand-1 (PDL-1)
  5. Example: Ipilimumab (Yervoy) targets Cytotoxic T Lymphocyte Associated-4 (CTLA-4)

Adverse Effects

Adverse Effects varies by type of targeted Chemotherapy
Bankruptcy ("Financial Toxicity")
1. Regimens are very expensive, and in some cases without efficacy to justify their use
2. Cancer patients often modify or fail to fill their cancer Chemotherapy prescriptions due to cost
3. Zafar (2013) Oncologist 18(4):381-90 [PubMed]
4. Ramsey (2016) J Clin Oncol 34(9): 980-6 [PubMed]
Head and Neck
1. Pituitary inflammation (hypophysitis)
  1. Occurs with CTLA-4 inhibitors and PD-L1 inhibitors
2. Dry Mouth
Endocrine
1. Hypothyroidism
2. Adrenal Insufficiency
3. Diabetes Mellitus (autoimmune)
Lung
1. Pneumonitis
Abdomen
1. Hepatitis
2. Pancreatitis
3. Enterocolitis
Musculoskeletal
1. Arthralgias
Skin
1. Rash
2. Vitiligo

References