PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
TL;DR: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab, and high somatic mutation loads were associated with prolonged progression-free survival.
Abstract: BackgroundSomatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. ResultsThe immune-related objective response rate and immune-related progression-free survival ...
Citations
More filters
TL;DR: Hao et al. as mentioned in this paper found that the loss of or inhibition of WRN, in MMR-defective cells, triggers DNA damage that leads to p53-dependent and p53independent PUMA activation that precipitates the onset of mitochondria-mediated apoptosis.
Abstract: Colorectal cancer (CRC) initiates in the large intestine (colon or rectum) and is a leading cause of cancer-related deaths in the United States in both males and females and across all racial and ethnic groups (1). As much as 16% of these patients harbor a cancer susceptibility gene pathogenic variant, such as mutations in the adenomatous polyposis coli gene, the DNA polymerase genes POLE or POLD1 or the base excision repair genes MUTYH or NTHL1 (2). The most prominent of these hereditary CRC syndromes include pathogenic mutations in genes of the mismatch repair (MMR) pathway, including MLH1, MSH2, MSH6, and PMS2 (2). Patients with MMR deficiency are classified with Lynch syndrome (3) and have a high incidence of many cancers in addition to CRC, including cancer of the stomach, endometrium, and ovaries, among others (2, 3). As such, there is a dire need to uncover new therapies that might be selective for MMR-deficient cancers such as CRC. In PNAS, Hao et al. (4) uncover the mechanism that leads to apoptosis for a recently identified targeted therapy approach for MMR-deficient CRC (Fig. 1). An active area of discovery for tumor targeted therapeutic approaches relies on synthetic lethality, whereby treatments are designed to exploit compensatory (synthetic lethal) relationships among biological pathways essential for tumor growth, one of which is uniquely defective in the tumor (5, 6). Such an approach, for example, has been highly effective for the treatment of breast cancer with BRCA1/BRCA2 deficiency or with defects in other homologous recombinant genes, shown to be selectively sensitive to inhibitors of the DNA damage response (DDR) signaling enzyme, PARP1, such as olaparib (7) or talazoparib (8). Recent efforts (6, 9–13) have indicated that MMR-deficient CRC tumor cells are highly sensitive to loss of expression of WRN, a RecQ-family ATPdependent helicase/bifunctional 3′-5′ exonuclease, pointing to a synthetic lethal relationship between WRN and the MMR pathway in CRC. Hao et al. (4) build on their lab’s expertise on the mechanism of p53-dependent cell death, further documenting the significance of the WRN/MMR synthetic lethal relationship. Importantly, they find that the loss of or inhibition of WRN, in MMR-defective cells, triggers DNA damage that leads to p53-dependent and p53-independent PUMA activation that precipitates the onset of mitochondria-mediated apoptosis (Fig. 1). MMR is a post-replicative DNA repair pathway that recognizes and repairs base-base mis-pairs and DNA strand misalignments that arise during DNA replication (14, 15). Such lesions or DNA replication errors are recognized by the MSH2/ MSH6 heterodimer (the MutSα complex) that in turn recruits the MLH1/PMS2 heterodimer (the MutLα complex) (16). The base-base or strand misalignment error is then corrected by excision of the ‘error-containing’ DNA strand followed by gap-filling DNA synthesis, improving the overall fidelity of DNA replication by ~1,000-fold (14, 16, 17). As such, pathogenic defects in MMR lead to elevated mutation rates (14, 18) and genetic variability characterized by microsatellite instability (MSI) (19, 20). Regions of the genome encoding microsatellites or tracts of short (2 to 4 base) tandem repeats are highly unstable when MMR is defective, giving rise to either expansions or contractions of these microsatellites (19, 20). Close to 15% of CRC is classified by high levels of MSI (also called MSI-high), whereas 85% are found to have chromosomal instability but with genetically stable microsatellite regions, defined as microsatellite stable (MSS) (21). WRN loss (via RNA interference or CRISPR/cas9-mediated gene knockout, KO) in MMR-deficient and MSI-high cells (9–13) leads to elevated DNA damage (DNA double-strand breaks, DSBs) and cell death (9), not seen in MSS cells (10). Interestingly, it is the helicase function of WRN that is required for viability of MMR-deficient cells, not the WRN exonuclease activity (9–11). WRN may help resolve abnormal genomic structures, such as long (TA)n repeat expansions (13), that accumulate in MMR-deficient and MSI-high cells (10, 11, 13). Upon loss of WRN in MMR-deficient/MSI-high cells, such genomic structures are likely not resolved, leading to an increase in DNA damage and the activation of the DDR signaling kinases ATM and CHK2. The increase in DSBs upon loss of WRN in MSI-high cells (10, 11, 13), with high prevalence of end-resected breaks (13), is in-line with an increase in ATM/CHK2 activation. Hao et al. (4) show in MSI CRC, but not MSS CRC, that WRN depletion triggers an increase in DNA damage, as measured by phosphorylation (activation) of ATM(Ser1981) and CHK2(Thr68). Further, they find that ATM inhibition suppresses the WRN loss-induced phenotype, highlighting the significance of DNA damage induced apoptosis following WRN inhibition in MMR-deficient CRC cells (Fig. 1). WRN dependency in MMR-deficient/MSI-high cells has been documented in over 60 preclinical models (12), and loss
2 citations
TL;DR: The immunune checkpoint inhibitor (ICI) therapy is a well-established treatment in several cancers, eg, malignant melanoma and non-small cell lung carcinoma and is used in metastatic disease as discussed by the authors.
Abstract: Colorectal cancer (CRC) is a common malignancy with a worldwide distribution. Despite bowel cancer screening programmes, the management of patients with metastatic disease is still an important and challenging problem. Immune checkpoint inhibitor (ICI) therapy is a well-established treatment in several cancers, eg, malignant melanoma and non-small cell lung carcinoma and is used in metastatic disease. The principle of this treatment is to use monoclonal antibodies to block the immune tolerance that commonly develops to tumor cells, therefore allowing host T-cell immunity to recognise and lyse cancer cells. The cellular receptors most commonly targeted by ICI therapy are cytotoxic T-lymphocyte-associated protein-4 and the programmed death 1/programmed death ligand 1 system. This review provides a scientific background to current ICI therapy and discusses the factors that predict response to this treatment. This is followed by a description of the emerging evidence for the use of ICI therapy in CRC and the utility of cellular pathology in stratifying patients for this treatment, especially when the systemic disease is present.
2 citations
TL;DR: A comprehensive review of the advances in the field of immune therapies for MSI-H/dMMR metastatic colorectal cancer was provided in this article, with a focus on the major randomized clinical trials that led to Food and Drug Administration approval of specific ICIs for this population, as well as the mechanisms of resistance to ICI therapy.
Abstract: Microsatellite instability‑high/deficient mismatch repair colorectal cancer (MSI‑H/dMMR CRC) is a molecular subtype characterized by high‑frequency mutations within DNA mismatch repair genes. Defects in the DNA mismatch repair machinery lead to subsequent frame‑shift mutations, resulting in the generation of frame‑shift peptides that serve as neoantigens. This has translated into exquisite sensitivity to immune checkpoint inhibitors (ICIs) and a significant clinical benefit from immune therapies in this patient population. The present article provides a comprehensive review of the advances in the field of immune therapies for MSI‑H/dMMR metastatic CRC, with a focus on the major randomized clinical trials that led to Food and Drug Administration approval of specific ICIs for this population, a detailed review of the molecular background responsible for tumor response, as well as the mechanisms of resistance to ICI therapy. Finally, ongoing investigations of other immunotherapeutic strategies to address and overcome the challenges that currently limit response and long‑term response to ICIs were presented.
2 citations
TL;DR: Conclusive evidence that secondary cytoreduction with HIPEC is essential awaits the results from ongoing randomised controlled trials.
Abstract: Background The role of secondary cytoreduction with hyperthermic intraperitoneal chemotherapy (HIPEC) is not clearly defined in recurrent platinum-sensitive ovarian cancer (PSOC). There is a paucity of studies on secondary cytoreduction with HIPEC in PSOC from developing countries like India. This study was done to assess the feasibility and safety of secondary cytoreduction and HIPEC in recurrent PSOC. Methods This was a prospective, non-randomised, open-label, phase 2 trial of secondary cytoreduction and HIPEC (Cisplatin 75 mg/m2 43°C over 60 minutes) in patients with recurrent platinum-sensitive epithelial carcinoma of ovary/fallopian tube/peritoneum done in a tertiary cancer centre from February 2016 to August 2019. The primary outcome was to assess the overall survival (OS) and the secondary outcomes were to assess the progression-free survival (PFS) and toxicity. Results Twenty-seven patients were screened and among them, 15 patients were included in this analysis with a median follow-up of 25 months. The mean cancer antigen (CA) 125 at the time of recurrence was 149 U/mL (range: 10-2,030 U/mL) and the median platinum-free interval was 21 months. The perioperative chemotherapy used was paclitaxel + carboplatin 53.3% (8/15), liposomal doxorubicin + carboplatin 40% (6/15) and none 6.5% (1/15). The median Peritoneal Carcinomatosis Index score was 8 (range: 3-25). The Clavien Dindo score was I, II and III in 6.7%, 26.7% and 13.3% patients, respectively. Recurrence was radiological and biochemical in 60% (9/15) and 7% (1/15), respectively. The most common site of recurrence was intra-abdominal (peritoneal). The median PFS and OS were 15 months (range: 0-34) and 26 months (range: 23-29), respectively. The grade 3 or 4 toxicity was 40%. Conclusion Secondary cytoreduction with HIPEC is feasible and safe in recurrent PSOC. Conclusive evidence that secondary cytoreduction with HIPEC is essential awaits the results from ongoing randomised controlled trials.
2 citations
01 Jan 2022
TL;DR: Different types of cancer immunotherapy are reviewed, the predominant mechanisms of immunotherapy resistance are elaborated, and several delivery strategies at the proof-of-concept or clinical trial phase that can overcome tumor immun therapy resistance are described.
Abstract: Immunotherapy is a promising treatment for cancer nowadays, which induces a long-lasting response in contrast to chemotherapy and radiotherapy. The immunotherapies, mainly including immune checkpoint blockade therapy, adoptive cell therapy, and therapeutic cancer vaccines, have yielded remarkable clinical outcomes in cancer patients. However, most of the patients did not benefit from immunotherapy due to primary resistance and only a small part of initial responders developed acquired resistance that relapsed after a period of treatment. Improving the efficacy of immunotherapy is necessary to understand the mechanisms of immunotherapy resistance, namely primary resistance and acquire resistance, and then develop combination therapies through various delivery strategies to overcome immunotherapy resistance. In this chapter, we review different types of cancer immunotherapy, elaborate the predominant mechanisms of immunotherapy resistance and describe several delivery strategies at the proof-of-concept or clinical trial phase that can overcome tumor immunotherapy resistance.
2 citations
References
More filters
TL;DR: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.
Abstract: Background Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. Methods We enrolled patients with advanced melanoma, non–small-cell lung cancer, castrationresistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. Results A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drugrelated adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006). Conclusions Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)
10,674 citations
Additional excerpts
...Thyroiditis, hypothyroidism, or hypophysitis 4 (10) 0...
[...]
TL;DR: Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
Abstract: To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase e (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
6,883 citations
TL;DR: Antibody-mediated blockade of PD-L1 induced durable tumor regression and prolonged stabilization of disease in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer.
Abstract: Background Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. Methods In this multicenter phase 1 trial, we administered intravenous anti–PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti–PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. Results As of February 24, 2012, a total of 207 patients — 75 with non–small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer — had received anti–PD-L1 antibody. The media...
6,812 citations
TL;DR: Treatment efficacy was associated with a higher number of mutations in the tumors, and a tumor-specific T cell response paralleled tumor regression in one patient, suggesting that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
Abstract: Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
6,215 citations
TL;DR: In situ analysis of tumor-infiltrating immune cells may be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies.
Abstract: The role of the adaptive immune response in controlling the growth and recurrence of human tumors has been controversial. We characterized the tumor-infiltrating immune cells in large cohorts of human colorectal cancers by gene expression profiling and in situ immunohistochemical staining. Collectively, the immunological data (the type, density, and location of immune cells within the tumor samples) were found to be a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer. The results were validated in two additional patient populations. These data support the hypothesis that the adaptive immune response influences the behavior of human tumors. In situ analysis of tumor-infiltrating immune cells may therefore be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies.
5,536 citations