scholarly journals Clinical Application of Adaptive Immune Therapy in MSS Colorectal Cancer Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Danyang Wang ◽  
Hangyu Zhang ◽  
Tao Xiang ◽  
Gang Wang
Keyword(s):  
Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Adoptive T Cell Therapy ◽  
Therapeutic Approaches ◽  
T Cell Therapy ◽  
Adaptive Immune ◽  
Immune Therapies ◽  
Colorectal Cancer Patients ◽  
Therapeutic Cancer Vaccines

Colorectal cancer (CRC) is one of the most common cancers worldwide. However, the treatment outcomes of immunotherapy in microsatellite-stable (MSS) CRC remain unsatisfactory. As the majority of CRC cases display a molecular MSS/mismatch repair-proficient (pMMR) profile, it is particularly meaningful to explore the clinical applications of adaptive immune therapy in MSS CRC patients. In this review, we summarized the therapeutic approaches of adoptive immune therapies, including cytokines, therapeutic cancer vaccines, adoptive T-cell therapy, and immune checkpoint inhibitors, in the treatment of MSS CRCs.

scholarly journals Immunotherapy, Inflammation and Colorectal Cancer

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 618 ◽  
Author(s):  
Charles Robert Lichtenstern ◽  
Rachael Katie Ngu ◽  
Shabnam Shalapour ◽  
Michael Karin
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
The United States ◽  
Chemotherapeutic Agents ◽  
Adoptive T Cell Therapy ◽  
Current Status ◽  
Cancer Type ◽  
T Cell Therapy

Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from intestinal epithelial cells in the colon and rectum, that are impacted by numerous factors including genetics, environment and chronic, lingering inflammation, CRC can be a problematic malignancy to treat when detected at advanced stages. Chemotherapeutic agents serve as the historical first line of defense in the treatment of metastatic CRC. In recent years, however, combinational treatment with targeted therapies, such as vascular endothelial growth factor, or epidermal growth factor receptor inhibitors, has proven to be quite effective in patients with specific CRC subtypes. While scientific and clinical advances have uncovered promising new treatment options, the five-year survival rate for metastatic CRC is still low at about 14%. Current research into the efficacy of immunotherapy, particularly immune checkpoint inhibitor therapy (ICI) in mismatch repair deficient and microsatellite instability high (dMMR–MSI-H) CRC tumors have shown promising results, but its use in other CRC subtypes has been either unsuccessful, or not extensively explored. This Review will focus on the current status of immunotherapies, including ICI, vaccination and adoptive T cell therapy (ATC) in the treatment of CRC and its potential use, not only in dMMR–MSI-H CRC, but also in mismatch repair proficient and microsatellite instability low (pMMR-MSI-L).

scholarly journals The Abscopal Effect: Could a Phenomenon Described Decades Ago Become Key to Enhancing the Response to Immune Therapies in Breast Cancer?

Breast Care ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. 443-449
Author(s):  
Hans-Christian Kolberg ◽  
Oliver Hoffmann ◽  
René Baumann
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Antitumor Immune Response ◽  
Abscopal Effect ◽  
Antitumor Effects ◽  
Effective Combination ◽  
Immunological Mechanisms ◽  
Immune Therapies

Background: The term “abscopal effect” was defined in 1953. In oncology the term is used to describe systemic antitumor effects triggered by local irradiation (nontarget effect). Although the mechanism of the abscopal effect is not completely understood yet, it has been demonstrated that in situ tumor vaccination, and the resulting antitumor immune response, is one of the key factors. Summary: The development of immune therapies has recently led to concepts combining local radiotherapy and immune therapy with the aim of enhancing the response to immune therapy by the immunological mechanisms summarized in the term abscopal effect. This concept has also been investigated in less immunogenic tumors such as breast cancer. Initial data are promising but the hypothesis that the combination of checkpoint inhibitors and local radiotherapy could be an effective combination in breast cancer has to be proven by ongoing trials. Substitution of local radiotherapy by local hyperthermia could be an option in selected cases. Key Messages: Combination of checkpoint inhibitors with local radiation or hyperthermia in breast cancer is a promising approach and could enhance the response rates generated by immune therapy alone through the antitumor immune response initiated by the abscopal effect.

Preclinical development of tumor-infiltrating lymphocyte therapy for metastatic colorectal cancer.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 95-95
Author(s):  
Donastas Sakellariou-Thompson ◽  
Marie-Andree Forget ◽  
Jason Roszik ◽  
Kyle R Jackson ◽  
Young Uk Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Ex Vivo ◽  
Total Yield ◽  
Adoptive T Cell Therapy ◽  
Small Subset ◽  
Autologous Tumor ◽  
Tumor Site ◽  
T Cell Therapy ◽  
Phase Ii Studies

95 Background: Immunotherapy has become an effective cancer therapy, particularly in the case of checkpoint blockade and adoptive T-cell therapy (ACT). ACT exploits the presence of tumor-infiltrating lymphocytes (TIL) by exponentially expanding their numbers ex vivo and re-infusing them into the patient in an autologous setting. With the effectiveness of TIL therapy already well established in multiple phase II studies in melanoma, there is a push to translate it to other cancers in need of improved therapies. Colorectal cancer (CRC) is a cancer where the presence of TIL has been strongly correlated with increased survival. Metastatic CRC (mCRC) has a poor outcome with median overall survival of less than 3 years. At present anti-PD1 therapy is only active in the small subset of mCRC patients (4%) that are MSI-high. We sought to evaluate the ability to generate and characterize TIL from patients with mCRC to provide a rationale for future TIL therapy in this disease. Methods: To assess the feasibility of utilizing TIL ACT for this patient population, we characterized the immune infiltrate of mCRC, TIL growth from tumor fragments (n = 24), as well as the TIL repertoire (n = 4) and anti-tumor potential in samples with available autologous tumor target. Results: Flow cytometry analysis detected a CD4-rich T-cell infiltration at the tumor site as well as a scarce yet activated CD8+ TIL population. The outgrowth of CD8+ TIL from tumor fragments in media containing IL-2 was potentiated by the addition of an agonistic 4-1BB antibody (Urelumab, BMS). Additionally, the use of a 4-1BB mAb improved the likelihood of growing TIL (63% [14/24] to 83% [20/24]) and increased the total yield of TIL grown. T-cell receptor sequencing showed enrichment in the tumor of CD8+ T-cell clones shared between the blood and tumor, suggesting selective expansion at the tumor site. Using IFNγ ELISPOT, CD8+ TIL from one patient with an MSS tumor were found to be reactive against a peptide derived from mutated TP53R116W restricted to HLA-B*39:01. Conclusions: It is possible to expand CD8+ T cells from microsatellite stable (MSS) mCRC that are able to target tumor antigens. Although preliminary, the initial data suggest the feasibility of TIL therapy for mCRC.

PD-L1 expression on tumor cells and tumor infiltrating immune cells in Chinese colorectal cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16111-e16111
Author(s):  
Jianjun Yang ◽  
Guanghui Xu ◽  
Jiyang Zheng ◽  
Kunli Du ◽  
Wei Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Cancer Treatments ◽  
Targeted Next Generation Sequencing ◽  
Biomarker Analysis ◽  
Programmed Death 1 ◽  
Cancer Types ◽  
Colorectal Cancer Patients

e16111 Background: Nowadays, immune checkpoint inhibitors (ICIs) targeting programmed death-1/ligand-1 (PD-1/PD-L1) have been an alternative in cancer treatments. Previous biomarker analysis found that response to anti-PD1/PD-L1 was associated with PD-L1 expression on tumor cells and/or tumor infiltrating immune cells in some cancer types. Explorations of IMblaze370 study demonstrated better survival outcome in colorectal cancer (CRC) patients with positive PD-L1 expression compared with those with negative PD-L1 expression in the atezolizumab group. Our study investigated PD-L1 expression profile in Chinese CRC population. Methods: PD-L1 expression on tumor cells or tumor infiltrating immune cells in 816 CRC tumors between January 01, 2017 and December 02, 2019 in 3D Medicines database was assessed by immunohistochemistry assay (SP263 or 22C3). We defined percentage of PD-L1 expression on tumor cells as tumor proportion score (TPS) strong positive ≥50%, moderate positive ≥5% and < 50%, weak positive ≥1% and < 5%, and negative < 1%. Similarly, we defined percentage of PD-L1 expression on infiltrating immune cells as immune proportion score (IPS) strong positive ≥10%, moderate positive ≥5% and < 10%, weakly positive ≥1% and < 5%, and negative < 1%. In addition, MSI status was evaluated with targeted next-generation sequencing covering 100 MSI loci. Results: 12 (1.5%) individuals had TPS as strong positive, 63 (7.7%) as moderate positive, 95 (11.6%) as weak positive and 646 (79.2%) as negative. Meanwhile, TPS of patients were 55 (6.7%) for strong positive, 49 (6.0%) for moderate positive, 34 (4.2%) for weak positive and 678 (83.0%) for negative, respectively. 16.9% in Chinese CRC patients here were defined as positive PD-L1 expression (IPS ≥1%), which is lower than the positive proportion of CRC in IMblaze370 study (39.9% for IPS ≥1%, P < 0.0001). The PD-L1 expression on tumor cells and on tumor infiltrating immune cells showed minimal overlap. In detail, only 29 (3.6%) patients exhibited simultaneously TPS positive (≥1%) and IPS positive (≥1%). Furthermore, IPS was not associated with MSI status (P = 0.9153), while TPS showed an association with MSI-H (P < 0.0001). In detail, 45.5% of MSI-H CRC patients were TPS positive. Conclusions: Chinese CRC patients express PD-L1 with 20.8% TPS positive and 17.0% IPS positive, and TPS positive were related to MSI-H. When studying the connection between the efficacy of PD1/PD-L1 inhibitors and PD-L1 expression, TPS and IPS detection would be both considered to engage.

scholarly journals Myeloid-Derived Suppressor Cells: Implications in the Resistance of Malignant Tumors to T Cell-Based Immunotherapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Houhui Shi ◽  
Kai Li ◽  
Yanghong Ni ◽  
Xiao Liang ◽  
Xia Zhao
Keyword(s):  
T Cell ◽  
Cancer Patients ◽  
Oncolytic Virus ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Immunological Response ◽  
Adoptive T Cell Therapy ◽  
Myeloid Derived Suppressor Cells ◽  
T Cell Therapy

T lymphocytes function as major players in antigen-mediated cytotoxicity and have become powerful tools for exploiting the immune system in tumor elimination. Several types of T cell-based immunotherapies have been prescribed to cancer patients with durable immunological response. Such strategies include immune checkpoint inhibitors, adoptive T cell therapy, cancer vaccines, oncolytic virus, and modulatory cytokines. However, the majority of cancer patients still failed to take the advantage of these kinds of treatments. Currently, extensive attempts are being made to uncover the potential mechanism of immunotherapy resistance, and myeloid-derived suppressor cells (MDSCs) have been identified as one of vital interpretable factors. Here, we discuss the immunosuppressive mechanism of MDSCs and their contributions to failures of T cell-based immunotherapy. Additionally, we summarize combination therapies to ameliorate the efficacy of T cell-based immunotherapy.

Immune Therapy Opportunities in Ovarian Cancer

2020 ◽  
pp. e228-e240 ◽  
Author(s):  
Lana E. Kandalaft ◽  
Kunle Odunsi ◽  
George Coukos
Keyword(s):  
Ovarian Cancer ◽  
Immune Therapy ◽  
Parp Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Clinical Activity ◽  
Small Subset ◽  
T Cell Therapy ◽  
Rational Combination ◽  
Major Direction ◽  
Immune Therapies

Immunotherapy has emerged as a highly promising approach in the treatment of epithelial ovarian cancer (EOC). Immune checkpoint blockade (ICB) therapy, PARP inhibitors (PARPis), neoantigen vaccines, and personalized T-cell therapy have been associated with encouraging clinical activity in a small subset of patients. To increase the proportion of patients who are likely to derive benefit, it will be important not only to generate sufficient numbers of antitumor T cells but also to overcome multiple inhibitory networks in the ovarian tumor microenvironment (TME). Therefore, a major direction is to develop biomarkers that would predict responsiveness to different types of immunotherapies and allow treatment selection based on the results. Moreover, such biomarkers would allow rational combination of immunotherapies while minimizing toxicities. In this review, we provide progress on immune therapies and future directions for maximally exploiting immune-based strategies for the treatment of ovarian cancer.

Novel synthetic immune modulators for the activation of tumor antigen-specific T cells.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15203-e15203
Author(s):  
Di Zhang ◽  
Lihua Shi ◽  
Susan Tam ◽  
Man-Cheong Fung
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Tumor Antigen ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Adoptive T Cell Therapy ◽  
In Vivo Studies ◽  
Target Specificity ◽  
T Cell Therapy

e15203 Background: Although checkpoint inhibitor immunotherapy and adoptive T-cell therapy revolutionized cancer treatments, such approaches suffer either from lack of target specificity for checkpoint inhibitors or inability to target intracellular tumor-related antigens from CAR-T therapy. Here, we report the development of novel Tavo Immune Modulator (TIM) biologics molecules which can specifically recognize tumor antigen-specific T cells through an engineered pMHC complex with peptides derived from intracellular tumor-related antigens. These molecules can selectively activate such T cells through engineered T cell co-stimulatory modulators for enhanced tumor cell killing. Methods: NY-ESO-1 and MAGE-A10 TIM molecules were constructed as fusions of HLA-A*02:01 MHC complexed with either NY-ESO-1 (157-165) or MAGE-A10 (254-262) epitope peptides at the N-termini and various T cell costimulatory modulators at the C-termini of IgG heavy and light chains. TIM molecules were expressed in Expi293 cells and purified by Protein A affinity chromatography. Specific binding of TIM with cancer specific T cells was evaluated by immunostaining. The activation and proliferation of tumor specific CD8+ T cells were confirmed in T cell activation and recall assays. Results: Both NY-ESO-1 and MAGE-A10 specific TIM molecules were generated which recognized corresponding tumor specific T cells. NY-ESO-1 TIM engineered with IL2 could activate NY-ESO-1 specific CD8+ T cell exclusively. Engineering additional T cell costimulatory factors along with IL2 on NY-ESO-1 TIM molecule could further boost T cell proliferation and activation in T cell recall assays. Besides NY-ESO-1, combinations of T cell costimulatory factors with MAGE-A10 TIM molecules enhanced specific T cell activation. Additional in vitro and in vivo studies are ongoing to demonstrate efficacy of such novel TIM molecules in eliminating different types of NY-ESO-1 and MAGE-A10 which are over-expressed on tumor cells. Conclusions: This study demonstrates the utility of NY-ESO-1 and MAGE-A10 TIM molecules in the selective recognition and activation of tumor antigen-specific T cells. Such novel biologics molecules may provide target specificity in tumor treatment, and potential targeting of intracellular tumor-related antigens presented as peptides in MHC complexes on cell surfaces. Selective activation of tumor-specific T cells may provide a unique method for the treatment of various solid tumors and warrants further investigation.

scholarly journals Understanding neutropenia secondary to intrinsic or iatrogenic immune dysregulation

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 504-513
Author(s):  
Kelly Walkovich ◽  
James A. Connelly
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Adaptive Immune Response ◽  
Immune Dysregulation ◽  
Inborn Errors ◽  
T Cell Therapy ◽  
Adaptive Immune

Abstract As a key member of the innate and adaptive immune response, neutrophils provide insights into the hematopoietic and inflammatory manifestations of inborn errors of immunity (IEI) and the consequences of immunotherapy. The facile recognition of IEI presenting with neutropenia provides an avenue for hematologists to facilitate early diagnosis and expedite biologically rationale care. Moreover, enhancing the understanding of the molecular mechanisms driving neutropenia in IEI—decreased bone marrow reserves, diminished egress from the bone marrow, and decreased survival—offers an opportunity to further dissect the pathophysiology driving neutropenia secondary to iatrogenic immune dysregulation, eg, immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy.

scholarly journals Cancer immunotherapy: current opportunities and perspectives

2021 ◽  
Vol 4 (2) ◽  
pp. 25-38
Author(s):  
O.Yu. Nikolaeva ◽  
R.V. Liubota ◽  
O.S. Zotov ◽  
R.I. Vereshchako
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Cell Therapy ◽  
Cancer Immunotherapy ◽  
Anticancer Agents ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Tumor Focus

Cancer immunotherapy is a relatively new and pro­mising method of treating neoplasms. Understanding the antigen-directed cytotoxicity of T-lymphocytes has become one of the central directions in involving the immune system in the fight against cancer. Basic research in this area has led to the invention of checkpoint inhibitors, adoptive T-cell therapy, and cancer vaccines. Cytokines can enhance the action of T-lymphocytes for their ability to directly stimulate effector and stromal cells in tumor focus and enhance recognition of tumor cells by cytotoxic effector cells. They were the first in cancer immunotherapy and remain relevant to this day. Today, immunotherapy is an effective treatment for most malignant tumors, including melanoma, non-small cell lung cancer, liver, stomach, bladder, cervical cancer, some types of breast cancer, lymphoma, etc. However, immunotherapy of some malignant tumors is ineffective, therefore, the development of new and improvement of existing immunotherapy agents is actively underway, and there is a hope that the indications for its use will expand. For this purpose, this review discusses the principles of action of various classes of immunotherapeutic anticancer agents, namely cytokines, immune checkpoint inhibitors, and adaptive T-cell therapy. The work highlights their indications, efficacy and toxicity from the use of each class of drugs, as well as the prospects for the development of immunotherapeutic anticancer drugs.

scholarly journals Efficacy and safety of immune checkpoint inhibitors in colorectal cancer: a systematic review and meta-analysis

2021 ◽  
Author(s):  
Tianni Zeng ◽  
Xiaojie Fang ◽  
Jinhua Lu ◽  
Yazhen Zhong ◽  
Xianlei Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Therapy Group ◽  
Meta Analysis ◽  
Efficacy And Safety ◽  
Significant Difference ◽  
Colorectal Cancer Patients

Abstract Background and objective Immune checkpoint inhibitor (ICI) therapies have shown promising prospects in colorectal cancer (CRC) immunotherapy; many clinical trials have been carried out. In this study, we sought to evaluate the efficacy and safety of ICI therapies in CRC by presenting a meta-analysis of relevant studies. Methods Databases including PubMed, Embase, Cochrane Library, and Web of Science were systematically searched for studies concerning the efficacy and safety of ICI in colorectal cancer. The reported odds ratio (OR) or weighted mean difference (WMD) with 95% confidence intervals (CIs) of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), treatment-related adverse events (TRAEs), and TRAEs ≥ 3 in the included studies were analyzed by fixed effects/random effects models. Results Three studies involving 667 patients with colorectal cancer were included in our meta-analysis. No significant difference between the immune checkpoint inhibitor therapies and conventional therapies in OS (WMD = 0.73, 95% CI − 3.09, 4.54; p = 0.71), in ORR (OR = 1.54, 95% CI 0.98, 2.40; p = 0.06), and in DCR (OR = 0.97, 95% CI 0.36, 2.61; p = 0.95). The median PFS of the ICI therapy group was shorter than that of the conventional therapy group (WMD =  − 0.10, 95% CI − 0.18, − 0.02; p = 0.02). At the same time, we also could not find a significant difference between the immune checkpoint inhibitor therapies and conventional therapies in TRAEs (OR = 1.56, 95% CI 0.11, 22.09; p = 0.74) and in TRAEs ≥ 3 (OR = 0.94, 95% CI 0.16, 5.65; p = 0.95). Conclusion Immune checkpoint inhibitor therapies could not improve all survival endpoints to advanced or metastatic colorectal cancer patients. Whether immune checkpoint inhibitors should be the first choice of therapies for colorectal cancer patients with undetermined microsatellite status or not able to determine microsatellite status needs more related studies to prove.

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