THE IMMUNE RESPONSE TO CANCER
Accumulating evidence indicates that immune surveillance and removal of immunogenic transformed cells presents a physiologic barrier to cancer development. Cancer cells can evolve a number of mechanisms to evade the immune system. They can reduce immune recognition by downregulation of major histocompatibility complex (MHC) class I antigens or by expressing immune suppressive proteins such as PD-L1. Cancer cells also have direct effects on the immune system. They secrete factors such as TGF-β, VEGF, and IL-10 that reduce the immune response, potentiate immune checkpoints, and recruit T reg cells and other immune suppressor cells. Exploitation of the immune response for cancer therapy is gaining momentum in the clinic. A major strategy in immune therapy is to boost the antitumor response by targeting immune checkpoints. Ipilimumab, a humanized antibody approved for the treatment of melanoma, enhances T-cell activation through blockade of CTLA-4-mediated co-inhibition. Similar therapies targeting PD-1/PD-L1–mediated checkpoints have also recently demonstrated substantial clinical effectiveness. Cancer cells also express antigens that can be used in vaccine therapies. These include cancer-testis antigens that are normally only expressed on germline cells (e.g., NY-ESO-1) and tissue-specific antigens. Sipuleucel-T is a cancer vaccine against prostatic acid phosphatase (PAP); it is approved for metastatic hormone-refractory prostate cancer. Evidence indicates that immune responses may also play a role in the therapeutic effect of antibodies designed to target specific oncogenes.
TARGETED CANCER THERAPIES
|THERAPEUTIC AGENT||TYPE||TARGET||DISEASE||INDICATION||COMPANION TEST|
|Small molecule||BCR-ABL||CML, ALL||Philadelphia chromosome positive||Cytogenetic analysis, FISH, PCR|
|Small molecule||CML and AML resistant to prior tyrosine kinase inhibitor therapy||Philadelphia chromosome positive||Cytogenetic analysis, FISH, RT-PCR|
|Imatinib||Small molecule||c-Kit||Gastrointestinal stromal tumours||CD117 (c-Kit) positive||Immunohistochemistry (c-Kit PharmDx)|
|Monoclonal antibody||EGFR||Colorectal cancer, head and neck||KRAS wild-type in colon cancer||PCR ( therascreenKRAS RGQ Kit)|
|Small molecule||EGFR||NSCLC||Mutant EGFR||PCR ( therascreenEGFR RGQ PCR Kit, cobas EGFR Mutation Test)|
|Small molecule||B-Raf||Melanoma||V600 mutant BRAF||PCR (THxID, cobas 4800 BRAF V600 Mutation Test)|
|Trastuzumab||Monoclonal antibody||Her2||Breast, stomach, gastroesophageal||Her2 positive||Immunohistochemistry (PATHWAY, InSite, Bond Oracle, HercepTest),
FISH (Inform, PathVysion, SPOT-Light, HER2 CISH PharmDx)
|Lapatinib||Small molecule||Her2, EGFR||Breast||Her2 positive, trastuzumab resistant|
|Everolimus||Small molecule||mTOR||Breast, pancreatic, renal cell, astrocytoma|
|Bevacizumab||Monoclonal antibody||VEGF||NSCLC, metastatic colorectal, metastatic kidney, glioblastoma|
ALL = acute lymphoblastic leukaemia; CML = chronic myelogenous leukaemia; FISH = fluorescence in situ hybridization; NSCLC = non–small cell lung cancer; PCR = polymerase chain reaction.