Active immunotherapy in cancer patients aims at specifically activating specialized immune cells known as T cells (a type of white blood cell). These cells are the police force of the immune system responsible for identifying and destroying diseased cells. Tumor-associated peptides (TUMAPs) such as those being developed by immatics, are derived from antigens overexpressed on tumor cells. By vaccinating patients with these TUMAPs, their T cells become activated to attack and destroy cells specifically expressing these tumor-associated peptides.
Tumor cells differ from healthy cells in the expression of tumor-associated proteins. HLA receptors on the cell surfaces display protein fragments (i.e. peptides) from cellular proteins to the outside. These peptides are pieces of larger proteins, which are degraded inside living cells into shorter fragments. These are then bound to HLA molecules and shuttled to the cell surface.
There are two classes of TUMAPs:
TUMAPs are short peptides (8 to 12 amino acids), which are intended to activate cytotoxic T cells (CTLs). Activated CTLs can directly kill tumor cells presenting such TUMAPs by secreting cytolytic substances, or by driving the target cell into apoptosis. CTLs play a dominant role in tumor elimination in active immunotherapy.
TUMAPs are long peptides (more than 15 amino acids), which are intended to activate T helper cells. Activated helper T cells assist cytotoxic T cells by locally increasing the concentration of certain cytokines, at the same time they have direct anti-angiogenic effects on the tumor, thus suppressing the growth of new blood vessels.
immatics discovers and develops both class I and class II peptides.
Even though TUMAPs are presented by most tumor cells, T cells are usually in a non-activated state in cancer patients. This is due to the fact that normal tissue does not inherently have the capacity to stimulate cells of the immune system just on its own. At the molecular level, we now know that this inability to stimulate T cells can chiefly be attributed to the absence of certain co-stimulatory surface-standing molecules. Administration (i.e., immunization, vaccination) of TUMAPs aims at activating (i.e. priming) T cells that will then specifically recognize the corresponding TUMAPs on the surface of tumor cells. This immune response, since it is specific to the tumor tissue, would not be expected to induce harmful adverse reactions in healthy tissues.
(1) Vaccination: TUMAPs are dissolved in water and administered intradermally together with an adjuvant, for example Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF).
(2) Priming: TUMAPs injected into the skin encounter dendritic cells residing just below the surface. TUMAPs are then loaded directly and externally onto surface-standing HLA molecules of the dendritic cells (DCs) at the administration site. These DCs then migrate to the lymph nodes where they encounter T cells. DCs deliver two signals to the T cells:
a. the specific signal via the HLA-peptide complex and
b. the co-stimulatory signal via special co-stimulatory molecules found only on the surfaces of dendritic cells.
The combination of both signals is known as “priming” and is necessary for activating previously inactive, naïve T cells, turning them into activated cytotoxic T cells.
(3) Proliferation: Once CTLs are primed by DCs, they start to grow rapidly in number (clonal proliferation). Soon thereafter they begin to leave the lymph nodes and blood vessels in search of cells displaying exactly the same HLA-peptide combination they were shown before on DCs in the process of priming. CTLs activated by TUMAP vaccination will seek out only tumor cells.
(4) Elimination: Once CTLs recognize the exact HLA-peptide combination again on a tumor cell, they eliminate the tumor cell by releasing cytolytic substances and/or by issuing an apoptotic death signal to the tumor cell.
However, priming of only one kind of CTL is usually insufficient to eliminate all tumor cells. Tumors are very mutagenic and are thus able to respond rapidly to CTL attacks by changing their pattern of expressed proteins, allowing them to escape from recognition by CTLs. In order to counter this tumor escape mechanism, immatics is developing products combining multiple TUMAPs (8-12 TUMAPs) which are given to the patient in a single injectable dose. In this way, a wide variety of different CTLs is primed, and CTLs can simultaneously attack the tumor at multiple target sites.