scholarly journals Good Tumor Response to Chemoradioimmunotherapy in dMMR/MSI-H Advanced Colorectal Cancer: A Case Series

2021 ◽  
Vol 12 ◽  
Author(s):  
Chengjing Zhou ◽  
Ting Jiang ◽  
Yajie Xiao ◽  
Qiaoxuan Wang ◽  
Zhifan Zeng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Case Series ◽  
Common Adverse Effect ◽  
Complete Response ◽  
Immune Checkpoint Blockade ◽  
Hematological Toxicity ◽  
Intratumor Heterogeneity ◽  
Dna Mismatch ◽  
Damage Repair ◽  
Repair Deficiency

PurposeImmune checkpoint blockade has led to a significant improvement of patient survival in metastatic colorectal cancer (CRC) with DNA mismatch repair-deficiency (dMMR)/microsatellite instability-high (MSI-H). However, not all these patients are sensitive to monoimmunotherapy. We firstly presented a case series of advanced dMMR/MSI-H CRCs treating with PD-1 inhibitor-based chemoradioimmunotherapy (CRIT).Methods and MaterialsWe assessed the short-term efficacy and safety of CRIT in advanced dMMR/MSI-H CRCs, and also did next-generation sequencing (NGS) assays.ResultsOur analysis included five advanced dMMR/MSI-H CRCs who have received toripalimab-based CRIT. Toripalimab was given 240mg every three weeks, and the radiation dose was 45-50 gray in 25 fractions. Chemotherapy regimens consisted of CAPOX in three patients, capecitabine in one patient, and mFOLFOX6 in one patient. Initially, two patients displayed complete response (CR), and three patients achieved partial response (PR) on imaging findings. Afterwards, one PR patient was confirmed pathological complete response after surgery, leading to three CR cases in total. Hematological toxicity was the most common adverse effect, and only two patients developed mild immune-related adverse effects besides. All the treatment-related adverse events were under control. Based on the NGS results, the median intratumor heterogeneity was 0.19 (range 0-0.957), which was less in CR patients than PR patients (P = 0.019). Genetic mutations at DNA damage repair genes and the JAK1 gene were also observed.ConclusionsFor advanced dMMR/MSI-H CRC, anti-PD-1 based CRIT is effective and safe. Further studies are required to better clarify the potential role and mechanism of CRIT as a viable therapeutic strategy in this population.

scholarly journals DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer

Cancer ◽  
2017 ◽  
Vol 123 (19) ◽  
pp. 3732-3743 ◽  
Author(s):  
Charité N. Ricker ◽  
Diana L. Hanna ◽  
Cheng Peng ◽  
Nathalie T. Nguyen ◽  
Mariana C. Stern ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Mismatch Repair Deficiency ◽  
Dna Mismatch ◽  
Hereditary Syndromes ◽  
Repair Deficiency ◽  
Dna Mismatch Repair Deficiency

scholarly journals Role of the Pathologist in the Diagnosis of Hereditary Non-Polyposis Colorectal Cancer

2004 ◽  
Vol 20 (4-5) ◽  
pp. 215-224 ◽  
Author(s):  
Jeremy R. Jass
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Tumor Infiltrating Lymphocytes ◽  
Dna Mismatch ◽  
Repair Deficiency ◽  
Dna Mismatch Repair Genes ◽  
Histological Criteria ◽  
Dna Microsatellite ◽  
Infiltrating Lymphocytes

The aim of this paper is to indicate how the pathologist may suspect a diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) on the basis of histological criteria and patient age alone. A single morphological feature, namely the presence of intra-epithelial lymphocytes (tumor infiltrating lymphocytes), identifies the majority of colorectal cancers (CRC) with the DNA microsatellite instability-high phenotype. A number of pathological criteria can help to distinguish HNPCC from sporadic MSI-H CRC, though age below 60 years is an important pointer towards HNPCC. Immunohistochemistry to demonstrate loss of expression of DNA mismatch repair genes serves as a highly reliable test of mismatch repair deficiency if antibodies to hMLH1, hMSH2, hMSH6 and hPMS2 are employed.

scholarly journals Mismatch repair deficiency is not sufficient to increase tumor immunogenicity

2021 ◽  
Author(s):  
Peter M K Westcott ◽  
Francesc Muyas ◽  
Olivia Smith ◽  
Haley Hauck ◽  
Nathan J Sacks ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Human Cancer ◽  
Tumor Cell Line ◽  
Immune Checkpoint Blockade ◽  
Mismatch Repair Deficiency ◽  
Dna Mismatch ◽  
T Cell Infiltration ◽  
Repair Deficiency ◽  
Tumor Mutational Burden

AbstractDNA mismatch repair deficiency (MMRd) in human cancer is associated with high tumor mutational burden (TMB), frameshift mutation-derived neoantigens, increased T cell infiltration, and remarkable responsiveness to immune checkpoint blockade (ICB) therapy. Nevertheless, about half of MMRd tumors do not respond to ICB for unclear reasons. While tumor cell line transplant models of MMRd have reinforced the importance of TMB in immune response, critical questions remain regarding the role of immunosurveillance in the evolution of MMRd tumors induced in vivo. Here, we developed autochthonous mouse models of lung and colon cancer with highly efficient ablation of MMR genes via in vivo CRISPR/Cas9 targeting. Surprisingly, MMRd in these models did not result in increased immunogenicity or response to ICB. Mechanistically, we showed this lack of immunogenicity to be driven by profound intratumoral heterogeneity (ITH). Studies in animals depleted of T cells further demonstrated that immunosurveillance in MMRd tumors has no impact on TMB but shapes the clonal architecture of neoantigens by exacerbating ITH. These results provide important context for understanding immune evasion in cancers with high TMB and have major implications for therapies aimed at increasing TMB.

Preliminary Experience of the Spanish Compassionate Use Registry of Bendamustine in Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4035-4035
Author(s):  
Beatriz Aguado Bueno ◽  
Isabel VicuÑa Andres ◽  
Laura Entrena ◽  
Felipe De Arriba ◽  
Isabel Krisnik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
De Novo ◽  
Common Adverse Effect ◽  
Previous Treatment ◽  
Complete Response ◽  
Clinical Results ◽  
Hematological Toxicity ◽  
Published Data ◽  
Compassionate Use ◽  
Grade 3

Abstract Abstract 4035 Introduction: Bendamustine is a dual alkylating agent with demonstrated efficacy in de novo multiple myeloma (MM) and in relapsed/refractory (R/R MM). We present the preliminary results from the experience of Spanish compassionate use registry of this agent in different treatment schedules of R/R MM, promoted by the GEM/PETHEMA Group (Benda-MMRR-11). This study has been approved by local ethical committee, CEIC, HUP, Madrid, Spain. Patients and Methods: 72 patients, 42 males and 30 females, with advanced R/R MM after several lines of previous treatment received a schedule containing Bendamustine (Levact®, Mundipharma, UK). Median age was 66 (35–86), with a median of 4 previous salvage lines (1–11). Bendamustine dose used ranged between 60 and 120 mg/m2 iv on days 1 and 2 for each 28 days cycle. The median of cycles was 2 (1–9). The combinations used were: Bendamustine + Prednisone in 27 patients, Bendamustine + Thalidomide + Prednisone in 11 cases, Bendamustine + Dexamethasone in 14 patients, Bendamustine + Bortezomib + Dexamethasone in 7 patients, Bendamustine + Bortezomib + Prednisone in 3 patients, Bendamustine + Thalidomide + Dexamethasone in 2 cases, Bendamustine monotherapy in 5 patients, Bendamustine + Thalidomide in 1 case, Bendamustine with Caelyx in 1 case and Bendamustine with Rituximab in 1 case. Results: In the 69 evaluable patients, the response was: overall response rate (ORR) 30.24%%, with complete response (CR) 11.5%, partial response (PR) 13.04%. Minimal response (MR) was 5.7%, and stable disease (SD) was 17.39%. Progression was documented in 52.1% of patients. In general, treatment was well tolerated; the most common adverse effect was hematological toxicity with grade 3–4 neutropenia in 31.8%, grade 3–4 thrombocytopenia in 30.4% and grade 3–4 anemia in 17.3%. Other toxicities included grade 3–4 infections in 27% of patients and grade 3–4 asthenia in 11.5%. Clinical results will be updated with more details regarding TTP, OS and efficacy and toxicity with each schedule. Comments: Bendamustine is an effective salvage therapy in patients with advanced R/R MM. Our results are consistent with previous published data in larger series of patients. More experience is needed with this agent to define the best combination and to assess its grade of efficacy that will be probably superior in earlier stages of myeloma evolution. Disclosures: Off Label Use: compassionate use.

Intratumoral CD3+ and CD8+ T-cell densities in patients with deficient DNA mismatch repair (dMMR) metastatic colorectal cancer (mCRC) receiving programmed death-1 (PD-1) blockade.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3532-3532
Author(s):  
Sakti Chakrabarti ◽  
Lucas J. Huebner ◽  
Heidi Diann Finnes ◽  
Andrea Muranyi ◽  
Shalini Singh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Disease Control ◽  
Objective Response ◽  
Response Duration ◽  
Complete Response ◽  
Automated Image Analysis ◽  
Medical Systems ◽  
Dna Mismatch ◽  
Cell Densities

3532 Background: Colorectal cancer with dMMR display heterogeneity in the extent of intratumoral T-cell infiltration which may explain their variable responsiveness to PD-1 blockade. We examined the association of intratumoral CD3+ and CD8+ T-cell densities (TCD) with objective response rate (ORR) and response duration in patients with dMMR mCRCs receiving pembrolizumab (PEM). Methods: Record review was performed on 12 patients with dMMR mCRC treated with PEM (200 mg intravenously every 3 weeks) after failure of prior chemotherapy [median no. of regimens was 1 (range 1-4)] between 01/2015 and 12/2017. CD3+ and CD8+ TCDs were analyzed in the primary tumor core (CT) and at the invasive margin (IM) by immunohistochemistry and automated image analysis to determine density score (0 to 100) for each T-cell subtype and compartment (Ventana Medical Systems, Inc.). Patients were categorized as 1) responders [CR (complete response) + PR (partial response)] vs. non responders [SD (stable disease) + PD (progressive disease)] per RECIST version 1.1, and 2) by duration of response (< or > 12 months). Results: Median follow-up post PEM was 19.5 (9-41) months. Responders included 2 CR and 5 PR; non-responders included 4 SD and 1 PD. The ORR and median time to response were 58.3% (7/12) and 12 weeks (range 9-40), respectively. CD3+ and CD8+ TCD scores were higher in responders vs. in non-responders as well as in patients who had disease control for > 12 months; differences were greatest for CD8+ CT (Table). Conclusions: Among patients treated with PEM, data suggest higher intratumoral CD3+ and CD8+ TCDs in responders versus non-responders and in those with a longer duration of disease control. If confirmed, TCDs may potentially predict responsiveness to PD-1 blockade in dMMR mCRCs. [Table: see text]

Successful treatment of metastatic colorectal cancer with synchronous BRAF V600E mutation and dMMR with BGB-A317

Immunotherapy ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 229-234
Author(s):  
Yi Cheng ◽  
Xue-Feng Fang ◽  
Han-Guang Hu ◽  
Jiang Wang ◽  
Li-Feng Sun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Colorectal Cancer Patient ◽  
Treatment Options ◽  
Abdominal Cavity ◽  
Postoperative Recurrence ◽  
Braf V600e ◽  
Dna Mismatch ◽  
Repair Deficiency ◽  
Pelvic Metastasis

Metastatic colorectal cancer with BRAF mutation is a type of highly invasive malignant tumor with poor prognosis and few treatment options. Here, we report a case of a BRAF-mutant and DNA mismatch-repair deficiency colorectal cancer patient with postoperative recurrence as well as abdominal cavity and pelvic metastasis, whose condition was relieved continuously after treatment with a new anti-PD-1 antibody, BGB-A317.

Sign in / Sign up

Export Citation Format

Share Document