Non-specific T cells (blue) recognize and kill target melanoma cells (red) but ignore non-target cells (green) in the presence of the drug, IMCgp100. Credit: Immunocore Ltd.
Our immune response is very effective at controlling most early and developing cancers. However, once cancer can be detected as a mass, tumor cells have very often evolved in their own version of natural selection to evade a patient’s immune system.
Over time, tumors develop different strategies to thwart the immune system. One way involves tumor cells becoming less visible to the immune system by altering and/or turning off biological processes that present proteins to immune cells. A second way is by establishing a potent immune-suppressive environment around the tumor. For example, pancreas tumor cells produce a molecule that attracts inflammatory cells to cloak the tumor, thereby preventing other immune cells from killing the cancer cells.
These obstacles make for a very difficult environment in which T cells can effectively attack tumors. In this regard, immunologists such as Michael Kalos, PhD, Director of the Translational and Correlative Studies Laboratory at Penn Medicine, are building a war chest of approaches to enhance the ability of T cells to attack as many cancer types as possible.
The immune system recognizes proteins (called antigens, immunologically) either fully intact on the surface of cancer cells or as small peptides derived from intracellular, surface bound, or secreted proteins presented on the surface in a complex with other molecules called HLAs. Intact surface molecules are recognized by antibodies produced by B cells, while the peptide complexes are recognized by the T-cell receptor complex (TCR) on T cells.
Potent antibodies can be made against most surface proteins expressed by tumor cells by immunizing animals such as mice, and such antibodies have been used clinically in a number of cancers. Isolating T cells with potent TCRs against proteins expressed by tumor cells is considerably more difficult since this cannot be done in animals, and our immune system selectively eliminates potent T cells against self, which is mostly what tumor cells are.
Although antibodies are powerful tools against tumors, they need to be administered on a regular basis and don’t usually have anti-tumor activity alone, but rather function as bridging agents to activate accessory immune cells. T cells, on the other hand, are cells that can survive in patients for an indefinite time period after a single infusion, and have a very potent and direct antitumor function.
Penn Med researchers are developing gene-engineering strategies to harness the potent activity of T cells against tumors. These approaches involve introducing T cell receptors that redirect T cells to recognize and destroy tumor cells within patients. In these approaches, T cells are isolated from patients, engineered and expanded to large numbers in the laboratory, and reintroduced into patients.
One approach is to create chimeric antigen receptors (CARs) which combine the potent antibody binding domains that bind to cancer cells with domains that signal T cells to target those cells. This approach, which is limited to targeting surface proteins, is being used with very promising results to treat patients with leukemias and is being developed for other types of cancers.
Another approach, developed collaboratively with colleagues at a UK company called Adaptimmune is to engineer in the lab a natural TCR that typically weakly recognizes tumor antigens to be more potent, and introduce those TCRs into patients’ T cells. This engineering of the natural TCR enables T cells to effectively recognize and kill cancer cells. Importantly, this approach is not limited to targeting only surface proteins but can be used to also target tumor-specific molecules that are inside the cells or secreted. Penn researchers together with colleagues at the University of Maryland are currently testing this approach to target multiple myeloma.
A third approach, developed by a UK company called Immunocore, involves engineering and using molecules called ImmTACs, for Immune Mobilizing mTCR Against Cancer. ImmTACs are one part enhanced TCR and another part derived from an antibody that recognizes CD3, a protein that is part of the TCR complex found on the surface of all T cells. The enhanced TCR component binds to tumor cells that express the corresponding peptide:HLA complex recognized by the TCR, while the antibody-CD3 part binds to the TCR from all T cells in the vicinity of the tumor, triggering them to be activated and kill target cells bound by the ImmTAC.
In a recent issue of Nature Medicine, scientists from Penn, Cardiff University, and Immunocore described the engineering and characterization of ImmTACs. Four different ImmTACs were evaluated and shown in both laboratory and animal studies to effectively redirect T cells to kill cancer cells expressing very low densities of peptide on their surfaces. The most advanced of the ImmTACs, called IMCgp100, is being evaluated in melanoma clinical trials in the UK and in the US at Penn and Washington University.
Liddy N, Bossi G, Adams KJ, Lissina A, Mahon TM, Hassan NJ, Gavarret J, Bianchi FC, Pumphrey NJ, Ladell K, Gostick E, Sewell AK, Lissin NM, Harwood NE, Molloy PE, Li Y, Cameron BJ, Sami M, Baston EE, Todorov PT, Paston SJ, Dennis RE, Harper JV, Dunn SM, Ashfield R, Johnson A, McGrath Y, Plesa G, June CH, Kalos M, Price DA, Vuidepot A, Williams DD, Sutton DH, & Jakobsen BK (2012). Monoclonal TCR-redirected tumor cell killing. Nature medicine PMID: 22561687