The future of affordable cancer immunotherapy

The treatment of cancer was revolutionized within the last two decades by utilizing the mechanism of the immune system against malignant tissue in so-called cancer immunotherapy. Two main developments boosted cancer immunotherapy: 1) the use of checkpoint inhibitors, which are characterized by a relatively high response rate mainly in solid tumors; however, at the cost of serious side effects, and 2) the use of chimeric antigen receptor (CAR)-T cells, which were shown to be very efficient in the treatment of hematologic malignancies, but failed to show high clinical effectiveness in solid tumors until now. In addition, active immunization against individual tumors is emerging, and the first products have reached clinical approval. These new treatment options are very cost-intensive and are not financially compensated by health insurance in many countries. Hence, strategies must be developed to make cancer immunotherapy affordable and to improve the cost-benefit ratio. In this review, we discuss the following strategies: 1) to leverage the antigenicity of “cold tumors” with affordable reagents, 2) to use microbiome-based products as markers or therapeutics, 3) to apply measures that make adoptive cell therapy (ACT) cheaper, e.g., the use of off-the-shelf products, 4) to use immunotherapies that offer cheaper platforms, such as RNA- or peptide-based vaccines and vaccines that use shared or common antigens instead of highly personal antigens, 5) to use a small set of predictive biomarkers instead of the “sequence everything” approach, and 6) to explore affordable immunohistochemistry markers that may direct individual therapies

Hipersensibilidad de tipo tardío y proliferación de linfocitos en respuesta a la infección mayor por leishmania en un grupo de niños en Jericó

The cellular response to Leishmania major was evaluated in vitro with a lymphocyte proliferation microtest, performed on 100 ?l of whole blood obtained by finger prick. The maximum time and optimum conditions for storage of fresh blood before testing were determined, and the ability of the assay to evaluate cellular immunity to Leishmania was compared to that of the classical Montenegro skin test. A positive correlation between the diameter of the skin induration and the stimulation index was demonstrated. Defining a positive skin test by induration ?5 mm, and a positive proliferation assay by a stimulation index >2·6 and a response ?3000 ct/min, we found a significant correlation between the 2 tests. The proliferation assay was less sensitive than the skin test, but somewhat more specific. Diagnostic specificities and sensitivities did not differ for the 2 tests

Phenotype-based variation as a biomarker of sensitivity to molecularly targeted therapy in melanoma

Transcriptomic phenotypes defined for melanoma have been reported to correlate with sensitivity to various drugs. In this study, we aimed to define a minimal signature that could be used to distinguish melanoma sub-types in vitro, and to determine suitable drugs by which these sub-types can be targeted. By using primary melanoma cell lines, as well as commercially available melanoma cell lines, we find that the evaluation of MLANA and INHBA expression is as capable as one based on a combined analysis performed with genes for stemness, EMT and invasion/proliferation, in identifying melanoma subtypes that differ in their sensitivity to molecularly targeted drugs. Using this approach, we find that 75% of melanoma cell lines can be treated with either the MEK inhibitor AZD6244 or the HSP90 inhibitor 17AAG

Human T Cell Crosstalk Is Induced by Tumor Membrane Transfer

<div><p>Trogocytosis is a contact-dependent unidirectional transfer of membrane fragments between immune effector cells and their targets, initially detected in T cells following interaction with professional antigen presenting cells (APC). Previously, we have demonstrated that trogocytosis also takes place between melanoma-specific cytotoxic T lymphocytes (CTLs) and their cognate tumors. In the present study, we took this finding a step further, focusing on the ability of melanoma membrane-imprinted CD8⁺ T cells to act as APCs (CD8⁺T-APCs). We demonstrate that, following trogocytosis, CD8⁺T-APCs directly present a variety of melanoma derived peptides to fraternal T cells with the same TCR specificity or to T cells with different TCRs. The resulting T cell-T cell immune synapse leads to (1) Activation of effector CTLs, as determined by proliferation, cytokine secretion and degranulation; (2) Fratricide (killing) of CD8⁺T-APCs by the activated CTLs. Thus, trogocytosis enables cross-reactivity among CD8⁺ T cells with interchanging roles of effectors and APCs. This dual function of tumor-reactive CTLs may hint at their ability to amplify or restrict reactivity against the tumor and participate in modulation of the anti-cancer immune response.</p></div

The effect of CD8⁺T-APCs on effector CTLs is mediated by tumor-derived pMHC.

<p><b>(A)</b> Ova-expressing EG7 and parental EL4 target cell lines (<i>Left column</i>) and target-entrained CD8⁺T-APC (generated following co-culture of OT-I CD8⁺ T cells with designated targets, <i>right column</i>) were labeled with Ova_257–264/H-2Kb-specific mAb (<i>black histogram</i>). <i>Grey histogram</i>, background staining with isotype control antibody. <b>(B)</b> Proliferation of OT-I CD8⁺ T cells stimulated with CD8⁺T-APCs. CFSE-labeled OT-I T cells were left untreated (no target) or co-cultured with the following T-APCs: OT-I CD8⁺ pre-incubated with EL4 (EL4) or OT-I CD8⁺ pre-incubated with EG7 cells (EG7). ConA stimulation was used as positive control (right). <i>Scale bars</i>, proliferating lymphocytes that divided at least twice. <i>Numbers</i>, percentage of dividing CD8⁺ T cells. Data are representative of two independent experiments.</p

CD8⁺ T-APCs induce degranulation of effector CTLs with different antigen specificity.

<p>(<b>A, B</b>) CD8⁺ clones with different antigen specificity were used as CD8⁺T-APCs and effector CTLs. Biotinylated effector CTLs were co-cultured with CD8⁺T-APCs, stained with anti-CD107A mAb and streptavidin-allophycocyanin and analyzed by flow cytometry. (<b>A</b>) The gp100_154–162-specific clone 1G2 was used as CD8⁺T-APC for the MART-1_26–35-specific CTL clones (2E2 and 2D11). <b>(B)</b> The MART-1_26–35-specific clones 2E2 and 2D11 were used as CD8⁺T-APC for the gp100_154–162-specific clone (1G2). Numbers in upper right quadrants indicate the percentage of CD107A⁺streptavidin⁺ lymphocytes, gated on the CD8⁺ population (effector CTLs). Data are representative of three independent experiments. (<b>C</b>) Graphic presentation of intra- and inter-clonal T cell cross talk.</p