The term 'immunogenic cell death' (ICD) denotes an immunologically unique type of regulated cell death that enables, rather than suppresses, T cell-driven immune responses that are specific for antigens derived from the dying cells. The ability of ICD to elicit adaptive immunity heavily relies on the immunogenicity of dying cells, implying that such cells must encode and present antigens not covered by central tolerance (antigenicity), and deliver immunostimulatory molecules such as damage-associated molecular patterns and cytokines (adjuvanticity). Moreover, the host immune system must be equipped to detect the antigenicity and adjuvanticity of dying cells. As cancer (but not normal) cells express several antigens not covered by central tolerance, they can be driven into ICD by some therapeutic agents, including (but not limited to) chemotherapeutics of the anthracycline family, oxaliplatin and bortezomib, as well as radiation therapy. In this Trial Watch, we describe current trends in the preclinical and clinical development of ICD-eliciting chemotherapy as partner for immunotherapy, with a focus on trials assessing efficacy in the context of immunomonitoring.

• Keywords
• Antigen-presenting cell, CAR T cells, autophagy, chemokines, cytokines, cytotoxic T lymphocyte, dendritic cell, endoplasmic reticulum stress, immune checkpoint blocker, type I interferon,
• MeSH
• Adaptive Immunity MeSH
• Immunogenic Cell Death MeSH
• Immunotherapy MeSH
• Humans MeSH
• Neoplasms * drug therapy   MeSH
• Antineoplastic Agents * therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Antineoplastic Agents * MeSH

CD52 is a glycoprotein expressed on normal as well as leukemic immune cells and shed as soluble CD52 (sCD52). We studied sCD52 levels in three CLL cohorts: the 'early', the 'high-risk', and the 'ibrutinib-treated'. The 'high-risk' patients had significantly higher sCD52 levels than the 'early' patients. For the 'early' patients, high sCD52 levels were associated with a significantly shorter time to first treatment. Regarding prognostic factors, no clear correlations with stage, IGHV, or beta-2-microglobulin were found; in a cox multivariate analysis of the 'early' patients, sCD52 and IGHV both had independent prognostic value. Following chemo-immunotherapy, sCD52 decreased in parallel with leukocytes while during ibrutinib treatment and ibrutinib-induced ymphocytosis, sCD52 decreased along with lymph node reductions. In vitro IgM stimulation of CLL cells led to increased sCD52 levels in the medium. Our findings indicate that sCD52 reflects disease activity and potentially treatment efficacy in CLL.

• Keywords
• CD52, CLL, chemo-immunotherapy, ibrutinib,
• MeSH
• Adenine analogs & derivatives   MeSH
• CD52 Antigen * blood   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * blood   drug therapy   immunology   MeSH
• Humans MeSH
• Piperidines MeSH
• Prognosis MeSH
• Antineoplastic Agents therapeutic use   MeSH
• Pyrazoles therapeutic use   MeSH
• Pyrimidines therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adenine MeSH
• CD52 Antigen * MeSH
• CD52 protein, human MeSH Browser
• ibrutinib MeSH Browser
• Piperidines MeSH
• Antineoplastic Agents MeSH
• Pyrazoles MeSH
• Pyrimidines MeSH

The ATM-p53 DNA-damage response (DDR) pathway has a crucial role in chemoresistance in CLL, as indicated by the adverse prognostic impact of genetic aberrations of TP53 and ATM. Identifying and distinguishing TP53 and ATM functional defects has become relevant as epigenetic and posttranscriptional dysregulation of the ATM/p53 axis is increasingly being recognized as the underlying cause of chemoresistance. Also, specific treatments sensitizing TP53- or ATM-deficient CLL cells are emerging. We therefore developed a new ATM-p53 functional assay with the aim to (i) identify and (ii) distinguish abnormalities of TP53 versus ATM and (iii) enable the identification of additional defects in the ATM-p53 pathway. Reversed transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) was used to measure ATM and/or p53-dependent genes at the RNA level following DNA damage using irradiation. Here, we showed that this assay is able to identify and distinguish three subgroups of CLL tumors (i.e., TP53-defective, ATM-defective and WT) and is also able to detect additional samples with a defective DDR, without molecular aberrations in TP53 and/or ATM. These findings make the ATM-p53 RT-MLPA functional assay a promising prognostic tool for predicting treatment responses in CLL.

• MeSH
• Ataxia Telangiectasia Mutated Proteins genetics   metabolism   MeSH
• Biological Assay MeSH
• Drug Resistance, Neoplasm genetics   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell drug therapy   genetics   metabolism   pathology   MeSH
• Doxorubicin pharmacology   MeSH
• Epigenesis, Genetic MeSH
• Humans MeSH
• Multiplex Polymerase Chain Reaction methods   MeSH
• Mutation * MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• Reverse Transcriptase Polymerase Chain Reaction methods   MeSH
• DNA Damage MeSH
• Antineoplastic Agents pharmacology   MeSH
• Gene Expression Regulation, Leukemic * MeSH
• RNA, Neoplasm genetics   MeSH
• Sensitivity and Specificity MeSH
• Vidarabine analogs & derivatives   pharmacology   MeSH
• Gamma Rays MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ATM protein, human MeSH Browser
• Ataxia Telangiectasia Mutated Proteins MeSH
• Doxorubicin MeSH
• fludarabine MeSH Browser
• Tumor Suppressor Protein p53 MeSH
• Antineoplastic Agents MeSH
• RNA, Neoplasm MeSH
• Vidarabine MeSH

Mutations or deletions in TP53 or ATM are well-known determinants of poor prognosis in chronic lymphocytic leukemia (CLL), but only account for approximately 40% of chemo-resistant patients. Genome-wide sequencing has uncovered novel mutations in the splicing factor sf3b1, that were in part associated with ATM aberrations, suggesting functional synergy. We first performed detailed genetic analyses in a CLL cohort (n=110) containing ATM, SF3B1 and TP53 gene defects. Next, we applied a newly developed multiplex assay for p53/ATM target gene induction and measured apoptotic responses to DNA damage. Interestingly, SF3B1 mutated samples without concurrent ATM and TP53 aberrations (sole SF3B1) displayed partially defective ATM/p53 transcriptional and apoptotic responses to various DNA-damaging regimens. In contrast, NOTCH1 or K/N-RAS mutated CLL displayed normal responses in p53/ATM target gene induction and apoptosis. In sole SF3B1 mutated cases, ATM kinase function remained intact, and γH2AX formation, a marker for DNA damage, was increased at baseline and upon irradiation. Our data demonstrate that single mutations in sf3b1 are associated with increased DNA damage and/or an aberrant response to DNA damage. Together, our observations may offer an explanation for the poor prognosis associated with SF3B1 mutations.

• MeSH
• Apoptosis MeSH
• Ataxia Telangiectasia Mutated Proteins metabolism   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell genetics   MeSH
• Gene Deletion MeSH
• Doxorubicin pharmacology   MeSH
• Phosphoproteins genetics   MeSH
• Genome, Human MeSH
• Histones metabolism   MeSH
• Imidazoles pharmacology   MeSH
• Cohort Studies MeSH
• Humans MeSH
• Ribonucleoprotein, U2 Small Nuclear genetics   MeSH
• Mutation * MeSH
• DNA Mutational Analysis MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Piperazines pharmacology   MeSH
• DNA Damage MeSH
• Prognosis MeSH
• Flow Cytometry MeSH
• Receptor, Notch1 genetics   MeSH
• Gene Expression Regulation, Leukemic * MeSH
• RNA Splicing Factors MeSH
• Vidarabine analogs & derivatives   pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• ATM protein, human MeSH Browser
• Ataxia Telangiectasia Mutated Proteins MeSH
• Doxorubicin MeSH
• fludarabine MeSH Browser
• Phosphoproteins MeSH
• H2AX protein, human MeSH Browser
• Histones MeSH
• Imidazoles MeSH
• Ribonucleoprotein, U2 Small Nuclear MeSH
• Tumor Suppressor Protein p53 MeSH
• NOTCH1 protein, human MeSH Browser
• nutlin 3 MeSH Browser
• Piperazines MeSH
• Receptor, Notch1 MeSH
• RNA Splicing Factors MeSH
• SF3B1 protein, human MeSH Browser
• TP53 protein, human MeSH Browser
• Vidarabine MeSH