Dendritic cells in cancer immunotherapy - a short review

Dendritic cells (DCs) are rare leukocytes that are uniquely potent in their recent application to therapeutic cancer vaccines. Isolated DCs loaded with tumour antigen ex vivo and administered as a cellular vaccine have been found to induce protective and therapeutic anti-tumour immunity. In the present report we describe the most common methods of culturing DCs and delivering tumour antigens and we summarise clinical trials of cancer immunotherapy using DCs-based vaccines

Dendritic cells in peripheral blood of patients with breast and lung cancer--a pilot study.

Dendritic cells (DCs) are regarded as the most potent antigen presenting cells that are well suited to activate T cells toward various antigens, such as tumor-associated antigens, due to their costimulatory activity. There is evidence that DCs are of diverse origin, with at least two types of myeloid and lymphoid precursors implicated in their generation. The recent reports demonstrated that the number and function of dendritic cells might change dramatically in cancer patients. In the present study we evaluated the percentage of myeloid and lymphoid DCs in patients with breast cancer, non-small cell lung cancer (NSCLC) and in the healthy donors. The percentage of both DC populations was significantly lower in patients with NSCLC than in the control group. In patients with breast cancer, the number of lymphoid DCs was significantly higher than in NSCLC patients. The obtained results suggest influence of pathological states on host immune system. The decrease in the number of DCs in the peripheral blood from cancer patients may be closely correlated with the type of tumour

Generation of dendritic cells from human peripheral blood monocytes - comparison of different culture media

Culture medium or medium supplement is one of the factors responsible for dendritic cell (DC) generation, but little is known about the influence of various media on DC culture. In our study we generated DC from adherent monocytes of human peripheral blood in the presence of GM-CSF, IL-4 and TNF-α. The following culture media were used: RPMI 1640 supplemented with 2% human serum albumin; RPMI 1640 supplemented with 2% TCH serum replacement; X-VIVO 15 and Panserin 501. Flow cytometry analysis revealed that in all media cells were CD83+ and lost CD14. Interestingly, the use of Panserin and RPMI with albumin preferentially gave rise to CD1a+ DC, whereas in X-VIVO and RPMI with TCH we observed both CD1a+ and CD1a-. Our results showed that RPMI with TCH yielded the highest percentage of cells expressing both CD80 and CD86 molecules and, in contrast to other media, the higher percentage of CD86+ cells in comparison to CD80+ cells

Monoclonal antibodies against immune checkpoints in immunotherapy of cancer patients

Od czasu opracowania przez Milsteina i Koehlera w 1975 roku technologii produkcji przeciwciał monoklonalnych, zastosowano je w niezliczonych eksperymentach naukowych, do celów diagnostycznych i terapeutycznych. W leczeniu chorych na nowotwory przeciwciała monoklonalne, blokujące receptory powierzchniowe nieprawidłowych komórek, pojawiły się pod koniec lat 90. ubiegłego wieku i okazały się niezwykle skuteczne w raku piersi (trastuzumab) lub jelita grubego (cetuksymab, panitumumab). Po upływie dekady nastąpił dynamiczny rozwój immunoterapii przeciwnowotworowej z udziałem przeciwciał monoklonalnych ukierunkowanych na immunologiczne punkty kontroli odpowiedzi odpornościowej. Zastosowanie przeciwciał anty-CTLA-4 (ipilimumab), anty-PD-1 (niwolumab, pembrolizumab) lub anty-PD-L1 (MPDL-3280A, MEDI-4736) ma na celu zniesienie anergii efektorowych limfocytów T wywoływanej przez komórki nowotworowe lub prezentujące antygen. Wspomniana anergia występuje wskutek połączenia różnych immunologicznych punktów kontroli (immune checkpoints), które znajdują się na wszystkich komórkach organizmu. Terapie tego rodzaju przynoszą często długotrwałą kontrolę choroby i rozwój swoistej odpowiedzi immunologicznej w takich nowotworach, jak czerniak i niedrobnokomórkowy rak płuca, a nawet rak nerki oraz trzustki. Są zazwyczaj mniej toksyczne od chemioterapii, choć do powikłań leczenia należą nierzadkie zjawiska autoimmunologiczne.Since 1975, when Koehler and Milstein had established the technology for the production of monoclonal antibodies, they were applied in numerous scientific experiments as well as for diagnostic and therapeutic purposes. In the late 90s of the last century, monoclonal antibodies which act by blocking surface receptors on abnormal cells, have proven to be very effective in the treatment of diseases such as breast cancer (trastuzumab) and colorectal cancer (cetuximab, panitumumab). After decade we observe a dynamic development of cancer immunotherapy involving monoclonal antibodies targeting immune checkpoints of immune response. The use of anti-CTLA-4 (ipilimumab), anti-PD-1 (niwolumab, pembrolizumab) or anti-PD-L1 (MPDL-3280, MEDI-4736) is intended to remove an anergy effector T cells induced by tumour cells or by antigen presenting cells. This type of therapy often results in long-term disease control and in development of a specific immune response in such malignancies as melanoma, non-small cell lung cancer, kidney and pancreatic cancer. They are generally less toxic than chemotherapy, but the treatment is associated with quite frequent autoimmune phenomena

Development of anticancer immunotherapy idea

W ciągu kilkudziesięciu lat doszło do znaczącej ewolucji koncepcji przeciwnowotworowej immunoterapii, polegającej na stopniowym odejściu od metod swoistej immunoterapii czynnej w kierunku stosowania przeciwciał skierowanych na immunologiczne punkty kontrolne. Wyniki badań klinicznych wykazały ograniczoną skuteczność „szczepionek” przeciwnowotworowych zawierających antygeny lub całe komórki nowotworowe w leczeniu zaawansowanych postaci czerniaka, niedrobnokomórkowego raka płuca i raka jelita grubego oraz wielu innych nowotworów. Immunoterapia z zastosowaniem komórek immunologicznych napotyka duże problemy metodologiczne, choć rozwój inżynierii genetycznej daje nadzieję na opracowanie skutecznych metod immunoterapii adoptywnej (np. z udziałem modyfikowanych limfocytów T cytotoksycznych). Natomiast przeciwciała anty-CTLA-4, anty-PD-1 i anty-PD-L1 umożliwiają uzyskanie długotrwałej kontroli choroby u niektórych pacjentów z różnymi typami nowotworów. Konieczne jest jednak poszukiwanie czynników predykcyjnych dla tego rodzaju terapii.Over the decades, significant evolution of anticancer immunotherapy idea has been seen, involving the gradual discontinuation of active specific immunotherapy methods towards the use of antibodies for immune checkpoints. Clinical studies have shown limited effectiveness of “vaccines” containing antigens or whole tumor cells in the treatment of advanced melanoma, non-small-cell lung cancer and colon cancer as well as many other tumours. Immunotherapy using immune cells encounters major methodological problems, although the development of genetic engineering gives hope for the development of effective methods for adoptive immunotherapy (eg. with modified cytotoxic T lymphocytes). In contrast, the use of anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies is possible to obtain long-term disease control in some patients with various types of cancer. The search for predictive factors of different immunotherapy methods is mandatory

Nivolumab in the treatment of thoracic cancer — new possibilities

Immune checkpoint inhibitors have significantly changed the treatment of patients with advanced non-small cell lung cancer in recent years. The value of nivolumab was initially assessed in patients previously treated with systemic therapy. The association of nivolumab with ipilimumab and the interaction of these antibodies on different immune checkpoints have proven effective in solid tumors (melanoma and renal cell carcinoma). The CheckMate-9LA study assessed the value of dual immunotherapy combined with platinum-based chemotherapy in the first-line treatment of advanced non-small cell lung cancer. A clinical benefit – prolonged overall survival in patients receiving combination therapy – was documented. The results of the CheckMate743 trial for patients with pleural mesothelioma provide a basis for changing the current management algorithm for patients with this diagnosis. Patients diagnosed with mesothelioma of a non-epithelioid type particularly benefit from two-drug immunotherapy compared to chemotherapy. Maintaining the safety of treatment using immunotherapy targeting two immune checkpoints remains the challenge

Predictive value of ERCC1 single-nucleotide polymorphism in patients receiving platinum-based chemotherapy for locally-advanced and advanced non-small cell lung cancer — a pilot study

Platinum-based chemotherapy is the main type of I-line treatment of advanced and non-operative NSCLC patients without EGFR gene mutation. The excision repair cross-complementation group 1 (ERCC1) is an enzyme that executes the incision of the damaged DNA strand and removes platinum-induced DNA adducts. We investigated whether ERCC1 gene polymorphism has an effect on the response to chemotherapy and survival in 43 patients with NSCLC treated with platinum-based chemotherapy. ERCC1 19007 T>C SNPs were assessed using a PCR-RFLP methods in DNA isolated from peripheral blood lymphocytes. Disease control occurred significantly (p = 0.045) more frequently in patients with CC or CT genotype compared to patients with TT genotype. Median PFS and OS for CC homozygous were 4 and 10.5 months, 4 and 12.5 months for CT heterozygous, but only 0.3 and 1.5 months for TT homozygous patients, respectively. The probability of PFS was significantly higher (HR = 0.438, 95% CI: 0.084–0.881, p = 0.03) and probability of OS was insignificantlyhigher (HR = 0.503, 95% CI: 0.129–1.137, p = 0.084) in patients with CC or CT genotype than in patients with TT genotype. Uncommon TT genotype of ERCC1 19007 T>C polymorphism could predict poor response and shortening of progression free survival in NSCLC patients treated with platinum-based I-line chemotherapy. The analysis of this polymorphism may serve as a promising tool in the qualification of advanced NSCLC patients for appropriate chemotherapy