The past few years have witnessed something of a renaissance in the field of cancer immunotherapy, relating largely to the clinical advances that have been associated with the development of ...monoclonal antibodies targeting the immune inhibitory co-receptors CTLA-4 and PD-1 and to the pursuit of genetically modified antigen-redirected adoptive T-cell therapies. These advances are based on a more substantial understanding of the factors restricting effective immune therapies that has been derived from the study of pre-clinical models of tumour growth in immune competent mice. Just as the recognition of the importance of positive co-stimulatory signaling has been instrumental to recent advances in the development of genetically modified antigen-specific adoptive cellular therapies, an increasing awareness of the ability of tumours to subvert multiple immune inhibitory pathways, effectively blunting the development or expansion of any anti-tumour immunity, is fostering the development of novel therapies that appear active as monotherapies but may achieve their greatest impact in combinatorial regimens. This mini-review will focus on attempts to target co-inhibitory members of the immunoglobulin superfamily.
Despite a number of preclinical studies demonstrating that the activity of anti-CTLA-4 antibodies in murine models of cancer relies on effector T-cell activation and regulatory T cell depletion, the ...activity of the clinical antibodies remains controversial. To decipher such mechanisms is critical to the development of novel and more potent immunotherapies.See related article by Sharma et al., p. 1233.
Double-stranded (ds) DNA virus infections often occur concomitantly in immunocompromised patients. We performed a systematic search of published in vitro activity for nine approved and ...investigational antivirals to understand the spectrum of in vitro activity against dsDNA viruses.
A literature search was performed (PubMed and the WoS Core Collection) using keywords related to: 1) targeted approved/developmental antivirals (acyclovir, artesunate, brincidofovir, cidofovir, cyclopropavir (filociclovir), foscarnet, ganciclovir, letermovir, and maribavir); 2) pathogenic dsDNA viruses; 3) in vitro activity. We summarized data from 210 publications.
Activity against ≤3 viruses was documented for maribavir (cytomegalovirus, Epstein-Barr virus), and letermovir, while activity against > 3 viruses was shown for ganciclovir, cidofovir, acyclovir, foscarnet, cyclopropavir, artesunate, and brincidofovir. The EC50 values of brincidofovir were the lowest, ranging from 0.001 to 0.27 μM, for all viruses except papillomaviruses. The next most potent agents included cidofovir, ganciclovir, foscarnet, and acyclovir with EC50 values between 0.1 μM and >10 μM for cytomegalovirus, herpes simplex virus, and adenovirus.
Most of the identified antivirals had in vitro activity against more than one dsDNA virus. Brincidofovir and cidofovir have broad-spectrum activity, and brincidofovir has the lowest EC50 values. These findings could assist clinical practice and developmental research.
•This is the first full summary of in vitro antiviral activity for 9 antivirals against human pathogenic dsDNA viruses.•Published in vitro activity often extended beyond the virus(es) covered by the labelled indication.•Most agents have good in vitro activity against individual or small subsets of dsDNA viruses that infect humans.•Based on an EC50 cut off of 10 μM, the spectrum of antiviral activity ranged from broadest to narrowest as follows:obrincidofovir > cidofovir > ganciclovir > artesunate > acyclovir > cyclopropavir (filociclovir) > maribavir > letermovir > foscarnet.
The continual interaction of the immune system with a developing tumor is thought to result in the establishment of a dynamic state of equilibrium. This equilibrium depends on the balance between ...effector and regulatory T‐cell compartments. Whereas regulatory T cells can infiltrate and accumulate within tumors, effector T cells fail to efficiently do so. Furthermore, effector T cells that do infiltrate the tumor become tightly controlled by different regulatory cellular subsets and inhibitory molecules. The outcome of this balance is critical to survival, and whereas in some cases the equilibrium can rapidly result in the elimination of the transformed cells by the immune system, in many other cases the tumor manages to escape immune control. In this review, we discuss relevant work focusing on the establishment of the intratumor balance, the dynamic changes in the populations of effector and regulatory T cells within the tumor, and the role of the tumor vasculature and its activation state in the recruitment of different T‐cell subsets. Finally, we also discuss work associated to the manipulation of the immune response to tumors and its impact on the infiltration, accumulation, and function of tumor‐reactive lymphocytes within the tumor microenvironment.
Allogeneic hematopoietic stem cell transplantation (SCT) is the treatment of choice for many malignant hematological disorders. Following recent improvements in non-relapse-related mortality rates, ...relapse has become the commonest cause of treatment failure. Infusion of donor lymphocytes can potentially enhance immune-mediated antitumor activity and offers a salvage option for some patients. This paper reviews the current literature on the efficacy of this therapeutic strategy.
The biology of adoptive cellular therapy with allogeneic immune cells to treat relapse across a spectrum of diseases in both the full intensity and reduced intensity hematopoietic SCT settings is explored. The review discusses the current limitations of the approach and reviews several new experimental strategies which aim to segregate the desired graft-versus-tumor effect from the deleterious effects of more widespread graft-versus-host reactivity.
Durable responses to DLI have been noted in chronic myeloid leukemia and responses have also been described in acute leukemia, multiple myeloma and chronic lymphoproliferative disorders. The new challenge in transplantation is to optimize DLI therapy in order to further improve patient outcomes.
Background.A retrospective study of the clinical, epidemiologic, and virologic features of norovirus gastroenteritis in 12 adult allogeneic hematopoietic stem cell transplant (HSCT) recipients. ...Methods.Norovirus infection was diagnosed by reverse-transcriptase polymerase chain reaction. Strains were genotyped by nucleic acid sequence of the most highly conserved region of the norovirus gene encoding the capsid S (shell) domain. Results.Ten of 12 patients presented with vomiting of short duration, but diarrhea was present in all. The median time from onset to norovirus diagnosis was 1 month (range, 0.25–6.0 months). Eleven patients were receiving immunosuppression when norovirus infection was diagnosed: 8 for graft-versus-host disease (GVHD) in an organ other than gut, 1 for previous gut GVHD, and 2 for presumed gut GVHD that proved to be norovirus gastroenteritis. Six patients required enteral or parenteral nutrition for severe weight loss. In 10 patients, diarrhea lasted a median of 3 months (range, 0.5–14 months) and virus was shed at a high level throughout. The remaining 2 patients died after 4 months of diarrhea (one died of unrelated complications, and the other died of malnutrition). The noroviruses found were GII (untyped), GII-3, GII-4, and GII-7 in 1, 1, 9, and 1 patients, respectively. Eleven of the 12 patients had acquired their infection in the community. Phylogenetic analysis of the GII-4 strains demonstrated that all differed. Conclusions.Noroviruses are a hitherto unsuspected cause of prolonged morbidity and mortality in adults after allogeneic HSCT. The use of reverse-transcriptase polymerase chain reaction to detect high viral load levels in feces distinguishes norovirus gastroenteritis from gut GVHD.
The finding that individual cancers contain many mutant genes not present in normal tissues has prompted considerable interest in the cancer epitope landscape. To further understand such effects, we ...applied in silico-based epitope prediction algorithms and high throughput post hoc analysis to identify candidate tumor antigens. Analysis of 1,152 peptides containing missense mutations previously identified in breast and colorectal cancer revealed that individual cancers accumulate on average approximately 10 and approximately 7 novel and unique HLA-A*0201 epitopes, respectively, including genes implicated in the neoplastic process. These data suggest that, with appropriate manipulation of the immune system, tumor cell destruction in situ may provide a polyvalent tumor vaccine without a requirement for knowledge of the targeted antigens.
The progression of a productive immune response requires that a number of immunological checkpoints be passed. Passage may require the presence of excitatory costimulatory signals or the avoidance of ...negative or coinhibitory signals, which act to dampen or terminate immune activity. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses, and the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand grouping represents the archetypal example of these immune regulators. In part the role of these checkpoints is to guard against the possibility of unwanted and harmful self-directed activities. While this is a necessary function, aiding in the prevention of autoimmunity, it may act as a barrier to successful immunotherapies aimed at targeting malignant self-cells that largely display the same array of surface molecules as the cells from which they derive. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate antitumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system. Such immunological molecular adjuvants are showing promise in early clinical trials. This review focuses on the results of the archetypal example of checkpoint blockade, anti-CTLA-4, in preclinical tumor models and clinical trials, while also highlighting other possible targets for immunological checkpoint blockade.
Cytomegalovirus (CMV) infection is common following allogeneic hematopoietic stem cell transplant (HSCT) and is a major cause of morbidity and increased mortality. Whilst pharmacotherapy can be ...effective in the prevention and treatment of CMV, these agents are often expensive, toxic and in some cases ineffective due to viral resistance mechanisms. Immunotherapeutic approaches are compelling and early clinical trials of adoptively transferred donor-derived virus-specific T (VST) cells against CMV have demonstrated efficacy. However, significant logistical challenges limit their broad application. Strategies to optimize VST manufacture and cell banking alongside scientific developments to enhance efficacy whilst minimizing toxicity are ongoing. This review will discuss the development of CMV-specific T-cell therapies, the challenges of widespread delivery of VSTs for CMV and explore how VST therapy can change outcomes in CMV infection following HSCT.
Background. Adoptive transfer of virus-specific T cells may accelerate reconstitution of antigen-specific immunity and limit the morbidity and mortality of viral infections following allogeneic ...hematopoietic stem cell transplantation. The logistics of producing virus-specific T cells has, however, limited the application of cellular therapies, particularly following the introduction of more-recent regulatory stipulations. Methods. We investigated the ability of cytomegalovirus-specific T cells, directly isolated from donor leucapheresates on the basis of interferon γ secretion, to restore antiviral immunity in a group of 25 patients following related-donor transplantation in a single-arm phase I—II study. Selected cells were administered early following transplantation, either after the detection of cytomegalovirus DNA by polymerase chain reaction—based surveillance or prophylactically between day 40 and day 50. Results. Cell selection was successful in all cases, yielding a product biased towards CD4⁺ over CD8⁺ T cells. The target cell dose of 1 × 10⁴ CD3⁺ T cells/kg of recipient weight contained a median of 2840 cytomegalovirus-specific CD4⁺ cells/kg and 630 cytomegalovirus-specific CD8⁺ cells/kg, with a median purity of 43.9% interferon γ—secreting cells. Expansions of both CD4⁺ and CD8⁺ cytomegalovirus-specific T cells were observed in vivo within days of adoptive transfer. These cells were predominantly terminally differentiated effector-memory cells and showed the same T cell receptor variable γ chain (TCRBV) —restriction as the infused cells. They offered protection from reinfection in the majority of patients. Conclusions. These data indicate that application of cytomegalovirus-specific T cells generated by direct selection using γ-capture is both feasible and effective in a clinical environment. These simple in vitro methodologies should allow more widespread application of virus-specific T cell immunotherapies.
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