Guide Immunological Aspects of Cancer

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It estimates the relative contribution of 22 different immune cell types of a mixture sample from both microarray and RNA-seq data by applying a machine learning support vector regression approach to perform feature selection, in which genes from the signature matrix are adaptively selected to deconvolve the mixture In a recent work, by applying CIBERSORT to thousands of tumor samples from TCGA and other public data banks and including every immune cell population in survival analyses, considerable variations among immune populations were observed to be cancer-specific, with many statistically significant associations.

This algorithm was developed by machine learning using a random forest classification approach, which was based on multitude decision trees, including parameters. The IPS profile differs between melanoma patients who respond or do not respond to immune checkpoint blockade ICB therapy for anti-PD-1 and anti-CTLA-4 , posing clear potential implications of this algorithm as a response predictor tool to immunotherapy Immunotherapeutic strategies and their relationship with immunological aspects of the tumors.

In the last two decades, several reports showing that T lymphocytes can recognize tumor antigens and shape the evolution of the disease have led to an improved understanding of the relationship between the immune system and tumors. This has culminated in the development of immunotherapies aimed to generate or enhance antitumor T cell responses by using vaccines, blocking antibodies, and adoptive cell transfer of genetically modified T lymphocytes.

These immunotherapeutic approaches are revolutionizing the treatment of different types of cancer, inducing long-term clinical benefits in patients who were resistant to conventional therapies. The increasing knowledge on the process of triggering and supporting an immune response has led to the identification of several molecules capable of regulating the immune response.

Laurence Zitvogel - Google Scholar Citations

An extensive description of the remarkable results obtained with ICBs is beyond the scope of this review, and we refer the reader to the excellent reviews addressing this topic 42 , In , a randomized phase 3 trial showed that the CTLA-4 antibody ipilimumab improves the overall survival in patients with metastatic melanoma 44 , which led to the first drug for checkpoint blockade approved by the Food and Drug Administration FDA in Combination therapies blocking CTLA-4 and PD-1 have been tested, and results have shown improved overall survival compared with monotherapy in patients with advanced melanoma 45 and metastatic renal cell carcinoma The combination of monoclonal antibodies agonistic to costimulating receptors in T lymphocytes, such as OX, CD28 or BB, could also be evaluated to further stimulate T cells 47 , Several aspects of the response to ICB can be addressed by characterizing the tumor in terms of immune response and mutation-related antigenic load.

Hypermutated tumors are capable of generating great amounts of neoantigens and may respond better to ICB Figure 2. Despite the absence of a precise biomarker of the immune checkpoint blockade response, elevated mutation load was shown to be a related factor in the CTLA-4 blockade response in melanoma One of the ICBs for PD-1 was recently approved for therapy in tumors bearing mismatch repair deficiency as the sole criterion for clinical indication, independent of the anatomical site of the tumor, representing a new paradigm for cancer treatment.

Predicting ICB responses in tumors can be challenging although extremely relevant considering the high economic costs of this therapeutic modality. Several initiatives are focusing on the development and implementation of refined algorithms, such as the IPS already mentioned, that can reliably predict responses in tumors. A different approach is evaluating response profiles soon after ICB administration. The aim of this approach is to identify dynamic response markers in the tumor microenvironment or in peripheral blood.

In , the United States, Europe and Australia approved an oncolytic virus immunotherapy for the treatment of advanced melanoma. The approved oncolytic virus is a herpes simplex virus type 1 HSV-1 engineered to express the human granulocyte-macrophage colony-stimulating factor GM-CSF , called Talimogene laherparepvec T-vec. Tumor regression can be achieved by infecting and directly killing the highly proliferating malignant cells. The dying tumor cells can expose more antigens and prime several T cells, generating a systemic tumor-specific immune response The insertion and expression of GM-CSF in the cell by the virus also leads to dendritic cell and macrophage recruitment and maturation within the tumor, which makes this therapy suitable for tumors without an important immune cell infiltrate The virus proteins themselves elicit an immune response within the tumor, causing more homing of immune cells.

Unfortunately, the immune response triggered by the virus itself induces an adverse effect in some patients, most notably in herpes seronegative patients injected with high viral doses. The side effects included local inflammation, erythema and febrile response, which could be managed by multidosing therapy: administer patients a low dose of virus for seroconversion and then administer a high dose A randomized phase III clinical trial with metastatic melanoma patients showed that T-vec reduced the injected lesions, uninjected nonvisceral lesions and uninjected visceral lesions, validating the therapy as a systemic immunotherapeutic approach.

The patients received the anti-PD-1 antibody pembrolizumab and multiple doses of T-vec. Inspired by the success of vaccines in infectious diseases, experimental vaccines were developed against different tumor antigens with the objective of inducing an endogenous response against the tumor. The first vaccines tested were TAA peptides 62 , because they are expressed by several patients and different types of tumors. However, despite years of research and development, the only cancer vaccine approved by the FDA to date is sipuleucel-T Provenge for the treatment of metastatic prostate cancer.

This vaccine consists of autologous blood monocytes loaded with a prostate cancer antigen prostatic acid phosphatase [PAP] fused to GM-CSF, leading to a modest survival benefit of only 4. The limited success of these vaccines is potentially related to the choice of target antigens, which focus on TAAs. While a vaccine targeting TAAs would benefit all patients who express the selected antigen s , the T cell clones that respond to them probably express low affinity T cell receptors TCRs or were tolerized by central and peripheral tolerance mechanisms. The high-throughput discovery of neoantigens allow the design of cancer vaccines targeting unique tumor antigens expressed by tumors especially for those hypermutated.

It has been proposed that an ideal neoantigen-based vaccine for cancer therapy should be composed of at least 20 epitopes in peptides greater than 20 amino acids long to favor cross-presentation and should include many neoantigens, thus preventing a reduction in immune system pressure by antigen loss by tumor mutations and enhancing immunological responses Two recent reports described the use of a personalized vaccine based on neoantigens identified in each patient to treat melanoma.

In one of them, long peptides harboring the neoantigen sequence were synthesized, considering multiple cuts for each amino acid-altered sequence to represent the neoantigen. Four peptide pools, totaling up to 20 peptides per patient, were administered in a series of five priming vaccine administrations to patients followed by two boosting steps. Approximately 25 months after vaccination, 4 of the 6 patients exhibited sustained remission with no sign of disease recurrence.

The two remaining patients were subjected to anti-PD1 ICB therapy and thus achieved remission after a few months.

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These results indicate the potential of ICB in unleashing the antitumor potential of suppressed T cell responses The other study used an RNA vaccine with ten neo-peptides, exclusive for each patient, encoded in two molecules. A maximum of 20 doses in a continuous treatment paradigm were administered without serious adverse events, and some patients generated a strong immune response.

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Complete responses were achieved in one patient after combination with anti-PD-1 and in another previously submitted to CTLA-4 blockade. One patient had a lymph node metastasis that stabilized after vaccination. The last patient was apparently tumor-free after the therapy, but died due to fast tumor progression. Further investigations revealed an acquired betamicroglobulin B2M deletion on both alleles, in line with its role in proper MHC class I antigen presentation.

This study suggests that vaccination using poly-neo-epitopes seems an effective way to prevent escaping clones and recurrent disease Together these data demonstrate the power and feasibility of neo-antigen-based vaccines. However, some challenges persist. For example, refinements are still needed to improve the accuracy of in silico prediction of neo-antigen immunity. The time feasibility, ideal administrations and costs of such approaches should also be further evaluated 5 , Despite the promising results obtained with neoantigens vaccines, this approach requires efficient in vivo priming and clonal expansion of antitumor T lymphocytes, steps that are often inhibited by the immunosuppressive environment induced by the tumor.

Moreover, the T cell clones responsive against neoantigens might be inhibited by peripheral tolerance mechanisms, such as PD-1 -mediated signaling. This opens the possibility of combining some of the kill and boost therapies for tumors such as peptide-based vaccines or oncolytic viruses to ICB in order to potentiate the engagement of the immune system by unleashing its potential while avoiding inhibitory signaling circuits to promote antitumor effects. In addition to cancer vaccines and ICBs, cellular therapies that also exploit the endogenous responses against tumor cells were developed, mainly for melanomas.

One approach derived from the observation that, in melanoma patients, a subset of T lymphocytes migrates and recognizes the tumor. These T lymphocytes are called tumor infiltrating lymphocytes TILs , and protocols have been developed to isolate and expand these cells in vitro 66 , The adoptive transfer of these cells achieved clinical responses in a significant proportion of metastatic melanoma patients, with robust results not previously observed with chemotherapy-based treatments Most tumors lack abundant TILs or even the capacity to generate efficient T cell responses on their own, even if TAAs or neoantigens are expressed by the transformed cells.

In the absence the stimulation of previous T cell responses, additional strategies can be developed to generate artificial T cell responses against the tumor. Several groups have cloned and described the T cell receptors TCRs that recognize these antigens, showing that T cells transgenically modified to express these antitumor TCRs can recognize and eliminate cancer cells in vitro and in vivo. These TCR-modified T cells were used in clinical trials for treatment of distinct types of cancer, such as sarcomas and melanomas, and induced significant clinical responses in patients 70 - Bioinformatics-based neoantigen determination pipelines allow a broader use of this approach, extended to cancers without described TAAs.

This personalized approach involves the analysis of tumor DNA or RNA sequences for the identification of neoantigens 75 , 76 combined with the identification of T cell clones that respond to these antigens. Recent reports show that the infusion of T cell clones against neoantigens can induce tumor regression in patients with cholangiocarcinoma 77 and colorectal cancer The immunotherapeutic approaches discussed so far require a pre-existent immune response against tumor neoantigens, which is more likely to occur in tumors characterized by high mutational load.

Tumour immunology and immunotherapy

Tumors with low mutation burden, e. Even frequently mutated tumors, with a considerable number of neoantigens, sometimes do not respond well to neoantigen vaccines The use of chimeric antigen receptor CAR -based immunotherapy in this setting has the potential to induce an immune response against tumor cells by redirecting T cell activity towards the tumor.

CARs are composed of an scFv derived from an antibody as an extracellular domain, a transmembrane domain and an intracellular domain derived from key signaling proteins of the TCR pathway CAR genes are normally transferred to T cells by a DNA-integrating vector, such as a retrovirus, a lentivirus or transposons CAR-expressing T lymphocytes can recognize a TAA of peptidic, glycidic or even lipidic nature on the surface of the target cells, activating the T cells and inducing their effector functions. Furthermore, the addition of costimulatory domains such as CD28 or BB to CARs second generation CARs increases the effector function and prolongs in vivo persistence of T cells, which has shown substantial efficacy in several preclinical tumor models Second-generation CARs targeting CD19 were the first to induce significant clinical benefit for patients, being used for the treatment of B cell malignancies 84 - The associated microenvironment established during tumor progression has a potential role in inhibiting CAR T cell migration and activity.

Indeed, preclinical studies have shown that cytokines, such as IL-4 87 or the tryptophan metabolizing enzyme IDO 88 , can inhibit the function of CAR T cells inside the tumor microenvironment. However, a recent published trial in which neuroblastoma patients were treated with anti-GD2 CARs in combination with lymphodepletion and PD-1 blockade showed no improvement in T cell function in vivo CAR therapies also carry an intrinsic risk of promoting on-target off-tumor adverse effects.

One patient was reported to have a fatal off-tumor effect due to pulmonary responses of a 3rd generation CAR specific for the erbb2 antigen Fine tuning of CAR functions can also be achieved by selecting proper CAR affinities 97 , 98 using combinations of CARs targeting different antigens 99 , or logic gate approaches for conditioning CAR activities to input signals to improve its safety profile 81 , Cancer immunotherapy has evolved from a long-lasting promise to an exciting reality in the last decade.

Our current rudimentary knowledge about the immune mechanisms underlying antitumor immune responses and tumor biology suggests that much higher tumor response rates will be achieved once we gain a deeper knowledge of tumor-immune system interactions. Combining immunotherapy modalities will also play a major role in next-generation immune-based therapeutic approaches, and we are currently witnessing only the beginning of this era.

After more than a century of unmet immunotherapy expectations, we can finally see decades of basic studies that described the operational mechanisms of the immune system setting the basis for the first generation of successful immunotherapies. The groundwork has been laid for the next generation of immune-based anticancer therapies. Relative importance of viral and neoantigens in cytotoxic reaction against murine leukaemia cells. Evidence for the IgG nature of complement-fixing CF antibodies to adenovirus type 12 hamster tumor neoantigens. J Immunol.

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Immunological Aspects of Neoplasia: A Rational Basis for Immunotherapy

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Immunological Aspects of Neoplasia: A Rational Basis for Immunotherapy

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