CAR-T cell. the long and winding road to solid tumors

Adoptive cell therapy of solid tumors with reprogrammed T cells can be considered the "next generation" of cancer hallmarks. CAR-T cells fail to be as effective as in liquid tumors for the inability to reach and survive in the microenvironment surrounding the neoplastic foci. The intricate net of cross-interactions occurring between tumor components, stromal and immune cells leads to an ineffective anergic status favoring the evasion from the host's defenses. Our goal is hereby to trace the road imposed by solid tumors to CAR-T cells, highlighting pitfalls and strategies to be developed and refined to possibly overcome these hurdles

Validation of Abnormal Self-Antigens as Targets for Tumor Rejection by CAR T Cells

Aberrant posttranslational modifications of cellular proteins represent a broad repertoire of putative tumor-specific targets. In general, vaccines targeting these aberrant self-antigens have only generated modest immune responses. In contrast, genetically modified T cells that express chimeric antigen receptors (CARs) demonstrate robust responses against associated targets, and have been clinically effective in treating hematologic cancers. However, in solid tumors the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-associated expression to which single-chain variable fragments (scFvs) can be designed. Thus, the majority of CAR targets to date have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we validate abnormal self-antigens as targets for tumor rejection through the use of a novel CAR. We targeted the cancer-associated Tn glycoform of MUC1 in a variety of cancers. The anti-Tn-MUC1 CAR demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These finding demonstrate the therapeutic efficacy of CAR T cells directed against abnormal self-antigens and the potential for targeting tumor-specific glycoproteins in future cancer immunotherapies

Hallmarks of Resistance to Immune-Checkpoint Inhibitors.

Immune-checkpoint inhibitors (ICI), although revolutionary in improving long-term survival outcomes, are mostly effective in patients with immune-responsive tumors. Most patients with cancer either do not respond to ICIs at all or experience disease progression after an initial period of response. Treatment resistance to ICIs remains a major challenge and defines the biggest unmet medical need in oncology worldwide. In a collaborative workshop, thought leaders from academic, biopharma, and nonprofit sectors convened to outline a resistance framework to support and guide future immune-resistance research. Here, we explore the initial part of our effort by collating seminal discoveries through the lens of known biological processes. We highlight eight biological processes and refer to them as immune resistance nodes. We examine the seminal discoveries that define each immune resistance node and pose critical questions, which, if answered, would greatly expand our notion of immune resistance. Ultimately, the expansion and application of this work calls for the integration of multiomic high-dimensional analyses from patient-level data to produce a map of resistance phenotypes that can be utilized to guide effective drug development and improved patient outcomes

Harnessing the immune system in glioblastoma.

Glioblastoma is the most common primary malignant brain tumour. Survival is poor and improved treatment options are urgently needed. Although immunotherapies have emerged as effective treatments for a number of cancers, translation of these through to brain tumours is a distinct challenge, particularly due to the blood-brain barrier and the unique immune tumour microenvironment afforded by CNS-specific cells. This review discusses the immune system within the CNS, mechanisms of immune escape employed by glioblastoma, and the immunological effects of conventional glioblastoma treatments. Novel therapies for glioblastoma that harness the immune system and their current clinical progress are outlined, including cancer vaccines, T-cell therapies and immune checkpoint modulators.N.B. is funded by Cancer Research UK. T.C. is funded by the University College London Hospitals Charity. P.M. is supported by the University College Hospital/University College London Biomedical Research Centre and the National Brain Appeal