INDI-integrated nanobody database for immunoinformatics.

Nanobodies, a subclass of antibodies found in camelids, are versatile molecular binding scaffolds composed of a single polypeptide chain. The small size of nanobodies bestows multiple therapeutic advantages (stability, tumor penetration) with the first therapeutic approval in 2018 cementing the clinical viability of this format. Structured data and sequence information of nanobodies will enable the accelerated clinical development of nanobody-based therapeutics. Though the nanobody sequence and structure data are deposited in the public domain at an accelerating pace, the heterogeneity of sources and lack of standardization hampers reliable harvesting of nanobody information. We address this issue by creating the Integrated Database of Nanobodies for Immunoinformatics (INDI, http://naturalantibody.com/nanobodies). INDI collates nanobodies from all the major public outlets of biological sequences: patents, GenBank, next-generation sequencing repositories, structures and scientific publications. We equip INDI with powerful nanobody-specific sequence and text search facilitating access to >11 million nanobody sequences. INDI should facilitate development of novel nanobody-specific computational protocols helping to deliver on the therapeutic promise of this drug format.

Hyperprogressive disease in early-phase immunotherapy trials: Clinical predictors and association with immune-related toxicities.

BACKGROUND: A subset of patients treated with immune checkpoint inhibitors experience an accelerated tumor growth rate (TGR) in comparison with pretreatment kinetics; this is known as hyperprogression. This study assessed the relation between hyperprogressive disease (HPD) and treatment-related toxicity and clinical factors. METHODS: This study reviewed patients with solid tumors who were enrolled in early-phase immunotherapy trials at Princess Margaret Cancer Centre between August 2012 and September 2016 and had computed tomography scans in the pre-immunotherapy (reference) and on-immunotherapy (experimental) periods. HPD was defined as progression according to Response Evaluation Criteria in Solid Tumors 1.1 at the first on-treatment scan and a ≥2-fold increase in TGR between the reference and experimental periods. Treatment-related toxicities requiring systemic therapy, drug delays, or discontinuation were considered clinically significant adverse events (CSAEs). RESULTS: Of 352 patients, 182 were eligible for analysis. The median age was 60 years, and 54% were male. The Eastern Cooperative Oncology Group performance status was 0 (32%) or 1 (68%). The Royal Marsden Hospital (RMH) prognostic score was 0/1 in 59%. Single-agent immunotherapy was given to 80% of the patients. Most patients (89%) received anti-programmed death (ligand) 1 antibodies alone or in combination with other therapies. HPD occurred in 12 of 182 patients (7%). A higher proportion of females was seen among HPD patients (P = .01), but no association with age, performance status, tumor type, RMH prognostic score, combination immunotherapy, or CSAEs was found. The 1-year overall survival rate was 28% for HPD patients and 53% for non-HPD patients (hazard ratio, 1.7; 95% confidence interval, 0.9-3.3; P = .11). CONCLUSIONS: HPD was observed in 7% of patients with solid tumors treated with immunotherapy. HPD was not associated with CSAEs, age, tumor type, or the type of immunotherapy but was more common in females.

Chronic lymphocytic leukemia (CLL) treatment: So many choices, such great options.

Within a period of just over a decade, managing chronic lymphocytic leukemia (CLL) has become more effective and yet more challenging than ever before. The important improvement in the treatment of CLL can be ascribed to the availability of many new options, mainly with the development of novel targeted therapies, such as ibrutinib, idelalisib, duvelisib and venetoclax. There are now newer tests that reliably define high-risk patients, and treatment plans can be tailored accordingly. Overall, this indeed is a new era in the treatment of patients with CLL. However, despite this progress, CLL remains an incurable disease and continues to remain challenging. In this brief review, the authors highlight the many great choices available to clinicians who manage patients with CLL and focus on the sequencing of these choices based on the available data.

Genetics and immunotherapy: using the genetic landscape of gliomas to inform management strategies.

Recent work in genetics has identified essential driver mutations in gliomas and has profoundly changed our understanding of tumorigenesis. New insights into the molecular basis of glioma has informed the development of therapies demonstrating considerable potential, including immunotherapeutic approaches such as peptide and dendritic cell vaccines against EGFRvIII. However, the selective targeting of one component of a dysregulated pathway may be inadequate for a durable clinical response, given the intratumoral heterogeneity of glioblastoma (GBM) and hypermutated profiles displayed by tumor recurrences. Immune checkpoint blockade with anti-cytotoxic T lymphocyte antigen-4 (CTLA) and anti-programmed cell death 1 (PD-1) have demonstrated encouraging results in clinical trials with other solid tumors, and recent data suggest that this type of therapy may be particularly useful for tumors with high mutational burdens. Although the survival for patients with GBM has remains grim, the use of immunotherapy may finally change patient outcomes.

Re-defining response and treatment effects for neuro-oncology immunotherapy clinical trials.

In much of medical oncology, including neuro-oncology, there is great interest to evaluate the therapeutic potential of immune-based therapies including vaccines, adoptive T cell strategies and modulators of immune checkpoint regulators such as cytotoxic T lymphocyte antigen 4 and programmed death 1. Immune-based treatments exert an indirect anti-tumor effect by generating potent, tumor-targeting immune responses. Robust anti-tumor immune responses have been shown to achieve encouraging radiographic responses across the spectrum of applied immunotherapeutics which are felt to be indicative of a bona fide anti-tumor effect. Conversely, worsening of imaging findings, particularly early in the course of immunotherapy administration, can be challenging to interpret with growing evidence demonstrating that at least a subset of such patients ultimately will derive meaningful clinical benefit. The immune related response criteria were generated to provide guidance regarding the interpretation of such complex imaging findings, for general medical oncologists prescribing immunotherapeutics. An analogous effort that addresses challenges associated with imaging assessment and incorporates nuances associated with neuro-oncology patients is underway and is referred to as the immunotherapy response assessment in neuro-oncology criteria.

[Biotherapies, immunotherapies, targeted therapies, biopharmaceuticals which word should be used?]. / Biothérapies, immunothérapies, thérapies ciblées, biomédicaments - De quoi faut-il parler ?

The ability to accurately describe and name medical advances is a prerequisite to foster public debates with scientists and physicians, and favour faith over fear among patients and citizens. Therapeutic antibodies are a good example of a medical breakthrough which has met with considerable clinical success, and which terminology has changed over the years. If the appellation serotherapy was appropriate a century ago, it has become obsolete. Recent names such as biotherapy, immunotherapy, targeted therapy, biopharmaceuticals have been introduced and are now commonly used, each of those can apply to therapeutic antibodies. It is thus interesting to question the real meaning of these different appellations. Our goal in this manuscript is to analyse the genesis of these terms but also to suggest how to simplify the terminology: biotherapy or targeted therapy need to be eliminated, as well as immunotherapy when communicating with non scientific public. It is recommended to favour the term biopharmaceuticals (biomédicaments in French), which clearly indicates the origin of these molecules, intermediate between chemical drugs and living biologics, whose borders need to be accurately defined also.

Immune approaches to the treatment of breast cancer, around the corner?

Immunotherapy for the treatment of breast cancer can be categorized as either (a) specific stimulation of the immune system by active immunization, with cancer vaccines, or (b) passive immunization, such as tumor-specific antibodies (including immune modulators) or adoptive cell therapy that inhibit the function of, or directly kill, tumor cells. We will present the current information and the future perspectives of immunotherapy in patients with breast cancer, including the prognostic role of tumor infiltrating lymphocytes, immune signatures, targeted therapies modulating the immune system, and tumor antigen cancer vaccines. Active immunotherapy in breast cancer and its implementation into clinical trials have been largely a frustrating experience in the last decades. The concept that the immune system regulates cancer development is experiencing a new era of interest. It is clear that the cancer immunosurveillance process indeed exists and potentially acts as an extrinsic tumor suppressor. Also, the immune system can facilitate tumor progression by sculpting the immunogenic phenotype of tumors as they develop. Cancer immunoediting represents a refinement of the cancer immunosurveillance hypothesis and resumes the complex interaction between tumor and immune system into three phases: elimination, equilibrium, and escape. Major topics in the field of immunology deserve a response: what do we know about tumor immunogenicity, and how might we therapeutically improve tumor immunogenicity? How can we modulate response of the immune system? Is there any gene signature predictive of response to immune modulators? The success of future immunotherapy strategies will depend on the identification of additional immunogenic antigens that can serve as the best tumor-rejection targets. Therapeutic success will depend on developing the best antigen delivery systems and on the elucidation of the entire network of immune signaling pathways that regulate immune responses in the tumor microenvironment.

Cellular immunotherapy of cancer.

Standard therapies for many common cancers remain toxic and are often ineffective. Cellular immunotherapy has the potential to be a highly targeted alternative, with low toxicity to normal tissues but a high capacity to eradicate tumor. In this chapter we describe approaches that generate cellular therapies using active immunization with cells, proteins, peptides, or nucleic acids, as well as efforts that use adoptive transfer of effector cells that directly target antigens on malignant cells. Many of these approaches are proving successful in hematologic malignancy and in melanoma. In this chapter we discuss the advantages and limitations of each and how over the next decade investigators will attempt to broaden their reach, increase their efficacy, and simplify their application.

[Local immunotherapy]. / Inmunoterapia local.

Specific immunotherapy, together with avoidance of the allergen and symptomatic treatment, forms part of the treatment of allergic pathology. The oldest, best known and most studied form is subcutaneous immunotherapy (SCIT), whose efficacy, both in the short and the long term, has been widely demonstrated in numerous studies. However, in spite of having been shown to be safe, it is not free of adverse effects and must be administered under the supervision of medical personnel. This has encouraged the search for new ways of administration of similar efficacy, with a good safety profile and good adherence on the patient's side. Sublingual immunotherapy (SLIT) is the most relevant of the different alternatives studied. In this alternative the antigen is administered in the form of drops under the tongue. There are different dosages of administration depending on the allergen involved. The optimum treatment dose has still to be determined, at present a wide range of dosages are found in comparison with subcutaneous immunotherapy. Its mechanism of action is little known although immunological changes have been observed in different studies. SLIT has shown a good safety profile with scarce secondary effects, normally of a local character. Similarly, different clinical tests have been carried out in which its efficacy has been shown in the treatment of respiratory allergy both in children and in adults. For this reason, although there are still unresolved data concerning this way of administering the immunotherapy, it has been proposed by the WHO as a valid alternative to SCIT.

Immunologic approaches to the management of pancreatic cancer.

Pancreatic cancer remains one of the most difficult cancers to treat; very few effective therapies are available, with surgery being the sole chance for cure-yet surgery is not a viable option for most pancreatic cancer patients. Immunotherapy has the potential to provide a non-cross-resistant mechanism of antitumor activity that can be integrated with surgery, radiation therapy, and chemotherapy. However, the inherent instability of the tumorgenome as well as tumor tolerance mechanisms are significant practical obstacles that must be overcome if immune-based approaches for pancreatic cancer can achieve its promise. Recent advances in both tumor immunology and vaccine design have already resulted in promising preliminary data from phase I studies, and additional trials are already in progress. This article summarizes some of the progress and challenges in immunotherapy research.

Immunotherapy of malignant melanoma.

Immunotherapy and biologic therapy of malignant melanoma are based on a sound scientific rationale and show promising preliminary results. As the nature of immune response to melanoma becomes further characterized, it is likely that more specific immune manipulations may be approached clinically. The fact that complete and partial remissions are induced in some patients with metastatic malignant melanoma by INF-alpha, IL-2, LAK cells, TIL cells, tumor vaccines, and the like clearly indicates a potential role for immunotherapy. As the overall response rates to these maneuvers are only in the range of 20%, more basic research is needed to understand more fully the immune mechanisms of tumor rejection. The combination of chemotherapy with biologic therapy has also provided promising leads. A major area waiting for development is the use of immunotherapy and biologic therapy as adjuvant treatment for the prevention of recurrence after surgical removal of high-risk Stage I/II and Stage III disease. The future of immunotherapy, either specific active immunization with appropriate vaccines or adoptive immunotherapy, must be based on well-defined molecules and antigenic systems, with appropriate enhancement based on the principles of immune reaction. Numerous strategies may be developed to enhance immune response, with resultant activation and proliferation of effector cells, including MHC- and non-MHC-restricted cytotoxic effector cells against tumor cells. The practice and principles of immunotherapy of human melanoma may be applied to other solid tumors that are resistant to chemotherapy and radiation therapy. Further experimentation in immunotherapy trials of melanoma may result in reliable and predictable clinical responses.

Chemotherapy in combination with biomodulation: a 5-year experience with cyclophosphamide and interleukin-2.

There are four classical forms of immunotherapy: active, adoptive, restorative, and passive, and perhaps a fifth form, cytomodulatory, the upregulation of tumor-associated and HLA antigens to make tumors more recognizable by the immune system. Our 5-year experience with low-dose cyclophosphamide (CY) (350 mg/m2) before low-dose interleukin-2 (IL-2) (21.6 million IU/m2/d x 5 d/wk x 2 wk per course by IV bolus) is reviewed as an example of combination chemotherapy and immunotherapy. Twenty-six percent (10 of 39 evaluable patients) of patients with melanoma had major clinical responses; one other patient (2%) has had more than 48 months of response after a 40% regression of all tumors. Median survival was 18 months for responders and 8 months for the group as a whole. Eleven of 41 patients (27%) lived at least 12 months and four (10%) lived at least 2 years. Liver metastases regressed in 4 of 10 cases, with responses in lung, adrenal, skin, and lymph nodes but no bone. Toxicity was tolerable. A correlation between cytolysis of lymphocytes against a natural killer-resistant melanoma cell line (LAK-like activity) was found, but the role of LAK cells in vivo remains uncertain. No effect was noted in 15 patients with renal cancer, but regressions of breast cancer were found in a shortened trial with 13 patients. While the necessity for CY has not been established in these studies, the regimen of CY + IL-2 as it stands appears to have some clinical efficacy in at least two cancers.

Inmunoterapia del Cáncer: transmisión experimental de una neoplasia de un hombre a un animal de distinta especie y ensayo de inmunoterapia pasiva de los tumores malignos / Cancer inmunotherapy

Para que la transmisión espontánea o experimental de las enfermedades infecciosas se realice, es necesaria la confluencia de dos factores fundamentales: Un germen virulento y un sistema inmuno deficiente. Se inoculó sangre de canceroso debidamente comprobado, a un animal de distinta especie, obteniéndose a los pocos días la reproducción del tumor original. Sin embargo, en el curso de estos trabajos se observó que la casi totalidad de los animales inoculados permanecían indemnes. La explicación de este hecho estaría a que el sistema inmune de éstos no sólo había aniquilado a cada uno de los componentes de la sangre inoculada, sino que como contrapartida, habría elaborado para este fin, anticuerpos. Esta circunstancias, permitió considerar teóricamente la posibilidad de intentar la inmunoterapia pasiva. Para comprobarlo se suministró al paciente canceroso sangre del animal inmunizado con la propia sangre del paciente en cuestión. Los resultados consignan tiempos de sobrevida hasta por diecisiete años en pacientes que habían sido desahuciados. Naturalmente para que este ensayo acerca de la inmunoterapia pasiva específica del cáncer tenga vigencia debe ser rigurosamente comprobado. Si se confirma, constituiría una nueva alternativa para el tratamiento del cáncer

[Cancer immunotherapy]. / Inmunoterapia oncológica.

A revision of the most promising clinical assays suggest that immunotherapy is useful for a certain number of selected patients. Immunotherapy cannot be used alone for primary treatment of cancer, excepting perhaps as local immunotherapy for readily accessible tumors. The most important role of immunotherapy is to be found in combination with other kinds of therapy, considering that it may restrain effectively hidden micrometastases that are the cause of relapse and fatal outcome. However, it is necessary to recognize that immunotherapy has shown until now a limited therapeutic efficacy.