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Fulltext Programmed cell death-ligand, thymidylate synthase and deleted in colorectal carcinoma biomarkers in colorectal carcinoma

Fauzah Abd Ghani, Reena Rehavu Zin, Maha Abdullah, Norhafizah Mohtarrudin, Ebenyi Emeka Onwe

Malaysian Journal of Medicine and Health Sciences, 2019;15(108):16-16.
MyJurnal

Introduction: It is well known that cancer cells evade the immune system with the help of programmed cell death protein 1 (PD-L1) molecule to remain undetected, causing abnormal proliferation of T-cells. PD-L1 expression on the surface of neoplastic cells inhibits cytotoxic T-cell responses which lead to negative regulation of cytokines and proliferation of T-cells. The deleted in colorectal cancer (DCC) gene belongs to the immunoglobulin superfamily. It is a candidate of the tumour suppressor gene by regulating apoptosis. DCC assessment gives an insight into progno-sis in patients with advanced stages of CRC. Thymidylate synthase (TYMS) is a highly conserved enzyme involved in DNA synthesis. TYMS has been an important target for cancer chemotherapy because of its central, rate-limiting role in de novo synthesis of thymidylate. Expression of PD-L1, TYMS and DCC has been demonstrated to confer a prognostic value in CRC but none have been completely validated for patient care. This study aimed to determine the prognostic and predictive potential of PD-L1, TYMS, and DCC biomarkers in CRC. Methods: The expression of these biomarkers was evaluated immunohistochemically in 91 formalin-fixed paraffin-embedded (FFPE) archival tumour samples from patients that underwent surgical resection. Results: There was high expression of DCC in most cases; 84.6% (77/91). TYMS expression at a high level score was 46.2% (42/91) and at low level was 53.8% (49/91). Majority of cases had low PD-L1 expression in 93.4% (86/91) cases and high expression was detected in 6.6% (6/94) of cases. In addition, there was a significant association between TYMS expression with gender (P < 0.05) with distribution of TYMS expression detected at high level was 76.2% in male and 23.8% in female. The Kaplan-Meier survival plot showed mean overall survival in patients with PD-L1 with high expression to be 22 months, which pre-dicts better survival. TYMS low expression showed mean overall survival of 90 which also indicated better survival. DCC high expression showed mean overall survival of 90 which indicated better survival. The correlation between the biomarkers and overall survival were not statistically significant. Conclusion: The results from this study suggest that PD-L1, TYMS and DCC expression could be used as biomarkers to predict treatment outcome in CRC. PD-L1 overexpression predicts patients who could benefit from anti-PD-1 and anti-PD-L1 immunotherapy whilst TYMS low expression predicts patients who could benefit from 5-fluorouracil therapy. DCC high expression tumours predicts a better prognosis and overall survival compared to DCC-negative tumours in advanced CRC.

Matched MeSH terms: Immunotherapy
Fulltext Cancer immunotherapy: current progress and applications

Pooi, Pooi Leong, Heng, Fong Seow

Malaysian Journal of Medicine and Health Sciences, 2006;2(2):1-26.
MyJurnal

Cancer immunotherapy is a form of treatment protocol for cancer patients that has been studied intensively over the last two decades. The undesirable side effects during the course of conventional treatment has lead to the development of immunotherapy as an alternative treatment modality. This approach encompasses the use of three different strategies with various immunotherapeutic modalities including (i) cytokines and monoclonal antibodies; (ii) activation of antigen presentation cells (APC) by using antigen-specific peptides or sources of antigens such as tumour lysate; and finally (iii) adoptive transfer of ex vivo activated autologous cytotoxic T-cells. Due to specific-targeting by antigen-specific monoclonal antibodies, dendritic cells and activated CD8+ T-cells, immunotherapy can eliminate tumour
cells efficiently but the normal tissues are unaffected. Despite years of investigation, the outcome of immunotherapy-based clinical trials are inconsistent with very low response rates from patients. Several mechanisms have been proposed to contribute to this failure including the presence of regulatory T-cells (Treg), immunomodulatory cytokines, and aberrant gene expression in tumour cells. This review summarises information from about 140 articles and review papers. In addition, it also provides an update on recent trends in combinational immunotherapy with conventional therapy and encouraging results have been obtained. Reevaluation of previous studies is necessary to fine-tune the design and approach of immunotherapy to ensure better treatment outcomes.

Matched MeSH terms: Immunotherapy
Fulltext Anti N-Methyl-D-Aspartate receptor encephalitis with ovarian teratoma: a dilemma in diagnosis

Lee, CL, Zainuddin AA, Abdul Karim AK, Yulianty A, Law, ZK, Md.Isa N, et al.

Journal of Surgical Academia, 2016;6(1):66-69.
MyJurnal

We report a rare case of altered mental status in a young patient with immature ovarian teratoma. A 22-year-old woman presented with seizures, hallucination, amnesia and orofacial dyskinesia. Examination and investigation revealed an ovarian massand asalphing-oophorectomy was performed. The histopathological examination result showed an immature teratoma grade 2 with thepresence of immature primitive glial tissue. Her CSF N-Methyl-D-Aspartic acid receptor (Anti-NMDAR) antibodytest was positive. N-Methyl-D-Aspartic acid receptor antibody associated limbic encephalitis is an autoimmune antibody-mediated neuropsychiatric disorder. Resection of the tumour and immunotherapy resulted in full recovery.

Matched MeSH terms: Immunotherapy
Insights into the chicken IgY with emphasis on the generation and applications of chicken recombinant monoclonal antibodies

Lee W, Syed Atif A, Tan SC, Leow CH

J Immunol Methods, 2017 08;447:71-85.
PMID: 28502720 DOI: 10.1016/j.jim.2017.05.001

The advantages of chicken (Gallus gallus domesticus) antibodies as immunodiagnostic and immunotherapeutic biomolecules has only been recently recognized. Even so, chicken antibodies remain less-well characterized than their mammalian counterparts. This review aims at providing a current overview of the structure, function, development and generation of chicken antibodies. Additionally, brief but comprehensive insights into current knowledge pertaining to the immunogenetic framework and diversity-generation of the chicken immunoglobulin repertoire which have contributed to the establishment of recombinant chicken mAb-generating methods are discussed. Focus is provided on the current methods used to generate antibodies from chickens with added emphasis on the generation of recombinant chicken mAbs and its derivative formats. The advantages and limitations of established protocols for the generation of chicken mAbs are highlighted. The various applications of recombinant chicken mAbs and its derivative formats in immunodiagnostics and immunotherapy are further detailed.

Matched MeSH terms: Immunotherapy
Guillain-Barré syndrome

Shahrizaila N, Lehmann HC, Kuwabara S

Lancet, 2021 03 27;397(10280):1214-1228.
PMID: 33647239 DOI: 10.1016/S0140-6736(21)00517-1

Guillain-Barré syndrome is the most common cause of acute flaccid paralysis worldwide. Most patients present with an antecedent illness, most commonly upper respiratory tract infection, before the onset of progressive motor weakness. Several microorganisms have been associated with Guillain-Barré syndrome, most notably Campylobacter jejuni, Zika virus, and in 2020, the severe acute respiratory syndrome coronavirus 2. In C jejuni-related Guillain-Barré syndrome, there is good evidence to support an autoantibody-mediated immune process that is triggered by molecular mimicry between structural components of peripheral nerves and the microorganism. Making a diagnosis of so-called classical Guillain-Barré syndrome is straightforward; however, the existing diagnostic criteria have limitations and can result in some variants of the syndrome being missed. Most patients with Guillain-Barré syndrome do well with immunotherapy, but a substantial proportion are left with disability, and death can occur. Results from the International Guillain-Barré Syndrome Outcome Study suggest that geographical variations exist in Guillain-Barré syndrome, including insufficient access to immunotherapy in low-income countries. There is a need to provide improved access to treatment for all patients with Guillain-Barré syndrome, and to develop effective disease-modifying therapies that can limit the extent of nerve injury. Clinical trials are currently underway to investigate some of the potential therapeutic candidates, including complement inhibitors, which, together with emerging data from large international collaborative studies on the syndrome, will contribute substantially to understanding the many facets of this disease.

Matched MeSH terms: Immunotherapy
Fulltext Xanthomatous Hypophysitis Presenting in an Adolescent Girl: A Long-Term Follow-Up of a Rare Case and Review of the Literature

Wong JSL, Nasruddin AB, Selveindran NM, Latif KA, Kassim F, Nair SB, et al.

AACE Clin Case Rep, 2021 02 01;7(3):220-225.
PMID: 34095493 DOI: 10.1016/j.aace.2021.01.008

Objective: Primary hypophysitis refers to the isolated inflammation of the pituitary gland not associated with other secondary causes. Among its histopathologic subtypes, xanthomatous is the rarest.
Methods: We describe a 22-year-old woman with xanthomatous hypophysitis (XH), its clinical progression over 8 years as well as the treatment effects of prednisolone and azathioprine. Our patient was first referred for severe short stature and delayed puberty at the age of 14 years.
Results: Investigations revealed multiple pituitary deficiencies. Magnetic resonance imaging showed a pituitary mass whereby a partial resection was performed. A full resection was not feasible due to the location of the mass. The histopathologic analysis of the tissue was consistent with XH. The results of secondary workout for neoplasm, infection, autoimmune, and inflammatory disorders were negative. After surgery, a progressive enlargement of the mass was observed. Two courses of prednisolone were administered with a significant reduction in the mass size. Azathioprine was added due to the unsustained effects of prednisolone when tapered off and the concern of steroid toxicity with continued use. No further increase in the mass size was noted after 6 months on azathioprine.
Conclusion: Glucocorticoid and immunotherapy are treatment options for XH; however, more cases are needed to better understand its pathogenesis and clinical progression.

Matched MeSH terms: Immunotherapy
Fulltext Antibody-dependent cellular phagocytosis of tropomyosin receptor kinase C (TrkC) expressing cancer cells for targeted immunotherapy

Lai PS, Usama SM, Kiew LV, Lee HB, Chung LY, Burgess K, et al.

Cancer Immunol Immunother, 2022 Sep;71(9):2099-2108.
PMID: 35032175 DOI: 10.1007/s00262-022-03147-y

Conventional cancer therapies such as chemotherapy are non-selective and induce immune system anergy, which lead to serious side effects and tumor relapse. It is a challenge to prime the body's immune system in the cancer-bearing subject to produce cancer antigen-targeting antibodies, as most tumor-associated antigens are expressed abundantly in cancer cells and some of normal cells. This study illustrates how hapten-based pre-immunization (for anti-hapten antibodies production) combined with cancer receptor labeling with hapten antigen constructs can elicit antibody-dependent cellular phagocytosis (ADCP). Thus, the hapten antigen 2,4-dinitrophenol (DNP) was covalently combined with a cancer receptor-binding dipeptide (IYIY) to form a dipeptide-hapten construct (IYIY-DNP, MW = 1322.33) that targets the tropomyosin receptor kinase C (TrkC)-expressed on the surface of metastatic cancer cells. IYIY-DNP facilitated selective association of RAW264.7 macrophages to the TrkC expressing 4T1 cancer cells in vitro, forming cell aggregates in the presence of anti-DNP antibodies, suggesting initiation of anti-DNP antibody-dependent cancer cell recognition of macrophages by the IYIY-DNP. In in vivo, IYIY-DNP at 10 mg/kg suppressed growth of 4T1 tumors in DNP-immunized BALB/c mice by 45% (p

Matched MeSH terms: Immunotherapy
Immunotherapies for the prevention and treatment of Staphylococcus aureus infections: updates and challenges

Chung PY

Pathog Dis, 2023 Jan 17;81.
PMID: 37422444 DOI: 10.1093/femspd/ftad016

Staphylococcus aureus is the leading cause of hospital-acquired infections and can cause a wide range of diseases from mild skin infections to invasive diseases including deep surgical site infections, life-threatening bacteremia, and sepsis. This pathogen remains a challenge to manage due to its ability to rapidly develop resistance to antibiotic treatment and to form biofilms. Despite the current infection control measures which involve mainly antibiotics, the burden of infection remains high. The 'omics' approaches have not led to the discovery of novel antibacterials at a pace sufficient to cope with the emergence of multidrug-resistant and biofilm-forming S. aureus, Hence, new strategies for anti-infective therapies need to be explored urgently. One promising strategy is harnessing the immune response to enhance the protective antimicrobial immunity in the host. This review discusses the potential of monoclonal antibodies and vaccines as alternatives to treat and manage infections caused by planktonic and biofilms of S. aureus.

Matched MeSH terms: Immunotherapy
Fulltext Successful treatment of anogenital warts with single dose Bacillus Calmette Guerin vaccine without prior sensitization in tuberculosis endemic country: Two case report

Achdiat PA, Suwarsa O, Hidayat YM, Shafiee MN, Dwiyana RF, Gunawan H, et al.

Hum Vaccin Immunother, 2023 Dec 31;19(1):2187591.
PMID: 36942667 DOI: 10.1080/21645515.2023.2187591

Anogenital Warts (AGWs) are benign proliferations caused by Human Papillomavirus (HPV) infection on the genital or anal areas. Various therapeutic options are available for the treatment of AGWs but there is no best or ideal therapy, and the recurrence of AGWs is significantly high. A promising new therapy that is currently being evaluated is immunotherapy with the intralesional Bacillus Calmette-Guérin (BCG) vaccine. Two cases of a 23-year-old woman and a 41-year-old man were presented with manifestations of condyloma acuminata type AGWs. The patients were immunocompetent and received single dose intralesional BCG vaccine on the largest lesion. Clinical improvements of AGWs lesions were noted starting on the 14th day after receiving therapy by the disappearance of some lesions with no recurrence and side effects. Intralesional BCG vaccine activates the immune system, treats other AGWs lesions that do not receive an intralesional injection, and also prevents recurrence. Although the intralesional BCG vaccine is effective for treating AGWs, further evaluation is still needed for its recurrence.

Matched MeSH terms: Immunotherapy
Fulltext Role of Interferons in the Development of Diagnostics, Vaccines, and Therapy for Tuberculosis

Chin KL, Anis FZ, Sarmiento ME, Norazmi MN, Acosta A

J Immunol Res, 2017;2017:5212910.
PMID: 28713838 DOI: 10.1155/2017/5212910

Tuberculosis (TB) is an airborne infection caused by Mycobacterium tuberculosis (Mtb). About one-third of the world's population is latently infected with TB and 5-15% of them will develop active TB in their lifetime. It is estimated that each case of active TB may cause 10-20 new infections. Host immune response to Mtb is influenced by interferon- (IFN-) signaling pathways, particularly by type I and type II interferons (IFNs). The latter that consists of IFN-γ has been associated with the promotion of Th1 immune response which is associated with protection against TB. Although this aspect remains controversial at present due to the lack of established correlates of protection, currently, there are different prophylactic, diagnostic, and immunotherapeutic approaches in which IFNs play an important role. This review summarizes the main aspects related with the biology of IFNs, mainly associated with TB, as well as presents the main applications of these cytokines related to prophylaxis, diagnosis, and immunotherapy of TB.

Matched MeSH terms: Immunotherapy/methods
Fulltext Conformational IgE Epitope Mapping of Der p 2 and the Evaluations of Two Candidate Hypoallergens for Immunotherapy

Reginald K, Chew FT

Sci Rep, 2018 02 21;8(1):3391.
PMID: 29467434 DOI: 10.1038/s41598-018-21792-1

Epitope mapping of Der p 2, a clinically important dust-mite allergen is the first step in designing immunotherapy hypoallergen vaccine candidates. Twenty-one single alanine mutants of Der p 2 were generated and their secondary structure was analysed using circular dichroism spectra. Only one mutant, K96A resulted in a misfolded protein. All mutants were tested for serum IgE reactivity using serum from dust mite allergic individuals by immuno dot-blots. Mutations to five residues, N10, E25, K77, K96 and E102 consistently showed reduced IgE reactions compared to wild-type Der p 2, and therefore these residues constitute the major IgE epitopes of Der p 2. Two mutants with consistent low IgE binding, K96A and E102A, were subsequently evaluated as hypoallergen candidates. IgG antibodies raised in mice against both mutants could inhibit human IgE-binding to WT Der p 2. Both mutants had intact T-cell epitopes as they were able to stimulate peripheral blood mononuclear cell proliferation similar to WT Der p 2. However, a switch in Th1:Th2 cytokine profile was not observed. In summary, we have identified the major conformational epitopes of Der p 2, and evaluated two Der p 2 hypoallergen vaccine candidates for immunotherapy.

Matched MeSH terms: Immunotherapy/methods
Conventional and unconventional therapies in typical and atypical chronic inflammatory demyelinating polyneuropathy with different clinical course of progression

Hung SKY, Hiew FL, Viswanathan S, Puvanarajah S

J Peripher Nerv Syst, 2018 Sep;23(3):183-189.
PMID: 30027593 DOI: 10.1111/jns.12282

Intravenous immunoglobulin (IVIG), corticosteroids and therapeutic plasma exchange (TPE) are evidence-based conventional treatments for chronic inflammatory demyelinating polyneuropathy (CIDP). In many centres, unconventional treatments are frequently used as alternatives. We evaluated the outcome of conventional and unconventional therapies in 31 CIDP patients. Overall response rate with conventional first-line immunotherapies was 77% (20/26), comparable between IVIG and corticosteroids (80% vs 70%). Use of TPE was limited. Treatment response among typical and atypical CIDP were comparable (76 vs 80%). Non-responders were patients with progressive form of typical CIDP and DADS. Majority (21/26, 81%) of patients with persistent neurological deficits received maintenance therapy. Two subgroups of patients frequently treated with maintenance immunosuppressants were those with improving or stable disease following first-line treatment (12, 57%) and those with progressive form of CIDP (2, 10%). Primary indications for immunosuppressant use were corticosteroids-sparing and additional immunosuppression effects. Nine (64%) patients with improving or stable disease given azathioprine were taken off corticosteroids after a median duration of 14 months (range 12-108). Two (14%) eventually achieved cure or clinical remission without treatment. Maintenance IVIg was given to 6 (29%) relapsing CIDP patients; none of achieved cure or remission after similar median duration of treatment. Less potent immunosuppressant drugs (azathioprine, mycophenolate mofetil, and methotrexate) were frequently used, with moderate adverse effect profiles. In resource limited setting, unconventional treatments were commonly used among CIDP patients with different clinical course of progression. In most cases, careful risk-benefit re-assessment is required to justify its further use.

Matched MeSH terms: Immunotherapy/methods*
The potential immune-eliciting cancer testis antigens in colorectal cancer

Chi Soh JE, Abu N, Jamal R

Immunotherapy, 2018 09;10(12):1093-1104.
PMID: 30185136 DOI: 10.2217/imt-2018-0044

The identification of cancer testis antigens (CTAs) has been an important finding in the search of potential targets for cancer immunotherapy. CTA is one of the subfamilies of the large tumor-associated antigens groups. It is aberrantly expressed in various types of human tumors but is absent in normal tissues except for the testis and placenta. This CTAs-restricted pattern of expression in human malignancies together with its potential immunogenic properties, has stirred the interest of many researchers to use CTAs as one of the ideal targets in cancer immunotherapy. To date, multiple studies have shown that CTAs-based vaccines can elicit clinical and immunological responses in different tumors, including colorectal cancer (CRC). This review details our current understanding of CTAs and CRC in regard to the expression and immunological responses as well as some of the critical hurdles in CTAs-based immunotherapy.

Matched MeSH terms: Immunotherapy/trends*
Validation of immunogenic PASD1 peptides against HLA-A*24:02 colorectal cancer

Soh JE, Abu N, Sagap I, Mazlan L, Yahaya A, Mustangin M, et al.

Immunotherapy, 2019 10;11(14):1205-1219.
PMID: 31478431 DOI: 10.2217/imt-2019-0073

Colorectal cancer is the third commonest malignancy in Asia including Malaysia. The immunogenic cancer-testis antigens, which are expressed in a variety of cancers but with limited expression in normal tissues except the testis, represent an attractive approach to improve treatment options for colorectal cancer. We aimed to validate four PASD1 peptides as the immunotherapeutic targets in colorectal cancer. First, PASD1 mRNA and protein expression were determined via real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. The PASD1 peptides specific to HLA-A*24:02 were investigated using IFN-y-ELISpot assay, followed by the cytolytic and granzyme-B-ELISpot assays to analyze the cytolytic effects of CD8+ T cells. Gene and protein expressions of PASD1 were detected in 20% and 17.3% of colorectal cancer samples, respectively. PASD1(4) peptide was shown to be immunogenic in colorectal cancer samples. CD8+ T cells raised against PASD1(4) peptide were able to lyze HLA-A*24:02+ PASD1+ cells. Our results reveal that PASD1(4) peptide represents a potential target for colorectal cancer.

Matched MeSH terms: Immunotherapy*
Fulltext Human mesenchymal stem cells inhibit the differentiation and effector functions of monocytes

Maqbool M, Algraittee SJR, Boroojerdi MH, Sarmadi VH, John CM, Vidyadaran S, et al.

Innate Immun, 2020 07;26(5):424-434.
PMID: 32635840 DOI: 10.1177/1753425919899132

Although monocytes represent an essential part of the host defence system, their accumulation and prolonged stimulation could be detrimental and may aggravate chronic inflammatory diseases. The present study has explored the less-understood immunomodulatory effects of mesenchymal stem cells on monocyte functions. Isolated purified human monocytes were co-cultured with human umbilical cord-derived mesenchymal stem cells under appropriate culture conditions to assess monocytes' vital functions. Based on the surface marker analysis, mesenchymal stem cells halted monocyte differentiation into dendritic cells and macrophages and reduced their phagocytosis functions, which rendered an inability to stimulate T-cell proliferation. The present study confers that mesenchymal stem cells exerted potent immunosuppressive activity on monocyte functions such as differentiation, phagocytosis and Ag presentation; hence, they promise a potential therapeutic role in down-regulating the unwanted monocyte-mediated immune responses in the context of chronic inflammatory diseases.

Matched MeSH terms: Immunotherapy/methods*
A variant e13a3 BCR-ABL1 fusion transcript in refractory adult B-cell acute lymphoblastic leukemia achieving complete remission with CAR-Tcell therapy

Phan CL, Tan SN, Tan SM, Kadir SSSA, Ramli NLM, Lim TO, et al.

Cancer Genet, 2021 01;250-251:20-24.
PMID: 33220656 DOI: 10.1016/j.cancergen.2020.11.003

Acute lymphoblastic leukemia (ALL) cases with e13a3 fusion transcripts are extremely rare. We report a 24-year-old male with Ph-positive (Ph+) ALL with an aberrant e13a3 fusion transcript treated with CD19-specific chimeric antigen receptor T-cell (CAR-T) therapy. He developed refractory disease post-chemotherapy induction, andreceived allogeneic hematopoietic stem cell transplantation (allo-HSCT) after salvage with imatinib in combination with chemotherapy regimen. Unfortunately, the patient relapsed after +90 days post-transplant. He was consented to CAR-T therapy trial and achieved complete remission, highlighting the efficacy of CAR-T treatment in relapsed-refractory B-ALL irrespective of the underlying genetic drivers in leukemia cells .

Matched MeSH terms: Immunotherapy, Adoptive*
The anti-idiotype vaccines for immunotherapy

Bhattacharya-Chatterjee M, Chatterjee SK, Foon KA

Curr. Opin. Mol. Ther., 2001 Feb;3(1):63-9.
PMID: 11249733

Certain anti-idiotypic antibodies that bind to the antigen-combining sites of antibodies can effectively mimic the three-dimensional structures and functions of the external antigens and can be used as surrogate antigens for active specific immunotherapy. Extensive studies in animal models have demonstrated the efficacy of these vaccines for triggering the immune system to induce specific and protective immunity against bacterial, viral and parasitic infections as well as tumors. Several monoclonal anti-idiotype antibodies that mimic distinct human tumor-associated antigens have been developed and characterized. Encouraging results have been obtained in recent clinical trials using these anti-idiotype antibodies as vaccines. In this article, we will review the current literature and discuss the potential of this novel therapeutic approach for various human cancers.

Matched MeSH terms: Immunotherapy/methods*
Fulltext Tocotrienols are good adjuvants for developing cancer vaccines

Hafid SR, Radhakrishnan AK, Nesaretnam K

BMC Cancer, 2010;10:5.
PMID: 20051142 DOI: 10.1186/1471-2407-10-5

Dendritic cells (DCs) have the potential for cancer immunotherapy due to their ability to process and present antigens to T-cells and also in stimulating immune responses. However, DC-based vaccines have only exhibited minimal effectiveness against established tumours in mice and humans. The use of appropriate adjuvant enhances the efficacy of DC based cancer vaccines in treating tumours.

Matched MeSH terms: Immunotherapy/methods
Fulltext Experimental production of clinical-grade dendritic cell vaccine for acute myeloid leukemia

Tan YF, Sim GC, Habsah A, Leong CF, Cheong SK

Malays J Pathol, 2008 Dec;30(2):73-9.
PMID: 19291915 MyJurnal

Dendritic cells (DC) are professional antigen presenting cells of the immune system. Through the use of DC vaccines (DC after exposure to tumour antigens), cryopreserved in single-use aliquots, an attractive and novel immunotherapeutic strategy is available as an option for treatment. In this paper we describe an in vitro attempt to scale-up production of clinical-grade DC vaccines from leukemic cells. Blast cells of two relapsed AML patients were harvested for DC generation in serum-free culture medium containing clinical-grade cytokines GM-CSF, IL-4 and TNF-alpha. Cells from patient 1 were cultured in a bag and those from patient 2 were cultured in a flask. The numbers of seeding cells were 2.24 x 10(8) and 0.8 x 10(8), respectively. DC yields were 10 x 10(6) and 29.8 x 10(6) cells, giving a conversion rate of 4.7% and 37%, respectively. These DC vaccines were then cryopreserved in approximately one million cells per vial with 20% fresh frozen group AB plasma and 10% DMSO. At 12 months and 21 months post cryopreservation, these DC vaccines were thawed, and their sterility, viability, phenotype and functionality were studied. DC vaccines remained sterile up to 21 months of storage. Viability of the cryopreserved DC in the culture bag and flask was found to be 50% and 70% at 12 months post cryopreservation respectively; and 48% and 67% at 21 months post cryopreservation respectively. These DC vaccines exhibited mature DC surface phenotypic markers of CD83, CD86 and HLA-DR, and negative for haemopoietic markers. Mixed lymphocyte reaction (MLR) study showed functional DC vaccines. These experiments demonstrated that it is possible to produce clinical-grade DC vaccines in vitro from blast cells of leukemic patients, which could be cryopreserved up to 21 months for use if repeated vaccinations are required in the course of therapy.

Matched MeSH terms: Immunotherapy/methods*
Systemic anti-CTLA-4 and intravesical Bacille-Calmette-Guerin therapy in non-muscle invasive bladder cancer: Is there a rationale of synergism?

Fahmy O, Khairul-Asri MG, Stenzl A, Gakis G

Med Hypotheses, 2016 Jul;92:57-8.
PMID: 27241256 DOI: 10.1016/j.mehy.2016.04.037

Although intravesical instillation of Bacille-Calmette-Guerin (BCG) immunotherapy was approved many decades ago as a first line therapy for intermediate to high-risk non-muscle invasive bladder cancer, its long-term efficacy is still arguable as a proportion of up to 30-40% of patients will develop recurrence or progression of their disease. Based on currently available data on the clinical application of checkpoint inhibitors in solid tumors, the mucosa-associated lymphoid tissue seems to be a main target for anti-CTLA-4 antibodies. In this manuscript we hypothesize that the combination of anti-CTLA-4 therapy with BCG might enhance the immune activity in the bladder submucosal tissue, and subsequently, improve oncological outcomes of NMIBC.

Matched MeSH terms: Immunotherapy/methods

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