Recent advances in cancer immunotherapy

Abstract

Cancer immunotherapy represents a major advance in the cure of cancer following the dramatic advancements in the development and refinement of chemotherapies and radiotherapies. In the recent decades, together with the development of early diagnostic techniques, immunotherapy has significantly contributed to improving the survival of cancer patients. The immune-checkpoint blockade agents have been proven effective in a significant fraction of standard therapy refractory patients. Importantly, recent advances are providing alternative immunotherapeutic tools that could help overcome their limitations. In this mini review, we provide an overview on the main steps of the discovery of classic immune-checkpoint blockade agents and summarise the most recent development of novel immunotherapeutic strategies, such as tumour antigens, bispecific antibodies and TCR-engineered T cells.

Keywords: Cancer immunotherapy; Cancer survival; Immune check point blockade; KRas; T cell receptor; p53.

Fig. 1

Schematic representation of the mechanism of action of scDb against mutant p53. Tumour cells as able to express on their surface specific peptides, including the R175H mutation of p53, presented by the HLA complex. The Bi-Specific Ab bridging T cells and tumour cell, H2-scDb (blue), includes a TCR arm as well as a p53R175 peptide complex arm. This binds via the p53R175 peptide (red), the peptide presenting complex (dark red/black). Therefore, the tumour cells to the T-cells can be bridged the HLA complex, and on the other arm the CD3/TCR complex from the T lymphocytes. Activation of the T-cell results in killing of the cancer cells, mediated by the release of cytotoxic molecules; in particular via the local cytokine storm includes granzymes, perforin, TNF-a as well as IFN-g, able to activate the programmed cell death program of the cancer cell. The effect of granzymes are mostly exerted through cell–cell contact. scDb, single-chain diabody; HLA, human leukocyte antigen; TCR, T cell Receptor; CD3, cluster of differentiation 3; IFNγ, Interferon gamma; TNF-α, Tumour Necrosis Factor alfa

Fig. 2

Purification and identification of the cell surface HLA"A" neo-antigen against p53 R175H. The Mutation-Associated Neoantigen—Selected Reaction Monitoring (MANA-SRM) pipeline starts by lysing the cells, and enriching HLA-bound peptides through immuno-precipitation with an antibldy targeting HLA molecules. HLA molecules together with their presented peptides are then eluted and dissociated. At this stage, the eluate containing the neo-antigenic peptides is filtred for lower molecular weights using a cut off of 3 kDa and the samples are lyophilized and analyzed for MANA-SRM using an improved hydrophilic interaction liquid chromatography (HILIC) cleanup; reduction at different pH using DL-dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP) is used before analysing the optimization of collision energies and fractionation. Manually examination and curation to exclude ions with excessive noise due to coelution with impurities is required to detect heavy isotope-labeled neo-antigens. See the original reference for details (Wang et al. Cancer Immunol Res, 2019)

Fig. 3

Schematic representation of the HPV-16 E7 specific TCR engineered T cell for patients with metastatic HPV-associated epithelial cancers. Simplified scheme showing the E711-19 specific TCR in a patient with a defect in the antigen processing is able to trigger a IFN response. A high-avidity TCR that targets HPV-16 E7 through the recognition of the E711–19 epitope complexed with HLA-A*02:01.Genetically engineered T cells are able to engage and kill HPV + tumour cell lines in vitro and mediate regression of HPV + tumor xenografts in vivo as well as in human patients. See for more details (Nagarsheth, Nat Med-2021[102]). Since the CD3 specific arm could activate both CD4 and CD8 cells, the cancer cell killing mechanism could be much more than IFNγ. In addition, the ability of IFNγ to induce HLA expression could be very important