Tumor immunology
Gabriel Virella in Medical Immunology, 2019
Our understanding of the immune responses against cancer and the mechanisms that tumors utilize to evade those immune responses has allowed us to develop novel and effective cancer immunotherapies. Current immune therapies have achieved unprecedented results in the treatment of cancer patients. As we look ahead, there are many approaches either in clinical trials or preclinical investigations that will likely improve on the current approaches. Combination therapies (e.g., checkpoint inhibitors with cytokine complexes, CAR-T cells combined with checkpoint inhibitors, BiTEs with checkpoint inhibitors) are the next logical step in therapy development. New targets for CAR T cells and BiTEs are currently in clinical trials and showing very encouraging results. Novel strategies to enhance ACT protocols are being developed. One of the most promising and exciting approaches in the field of cancer immunotherapy is the development of neoantigen-specific therapies. By determining tumor-specific mutations and identifying immunogenic neoepitopes, therapies such as vaccines or T-cell therapies can be developed, opening the door for the development of personalized, tumor-specific immune therapies.
Immunomodulatory Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Successful production of TILs has also been achieved from solid tumor types other than melanoma (e.g., breast, cervical, gastrointestinal, head and neck, ovarian, and non-small-cell lung tumors). Thus, the challenge for the development of TIL therapies for other tumor types is not obtaining and expanding the TILs but the heterogenicity of the mutational and neoantigen burden. This highlights the need to develop tools to accurately select and enrich for subset T-cell populations. Nonetheless, numerous clinical trials are underway utilizing studying the efficacy of TIL therapies in bladder, lung (i.e., NSCLC), and ovarian cancers. For example, Iovance Biotherapeutics recently presented the results of an ongoing Phase II clinical trial investigating the use of TIL therapy in cervical cancer. This trial achieved an ORR and PR of 44.4% and 33.3%, respectively, with 78% of patients achieving a reduction in tumor burden.
Biomarker-Based Phase II and III Clinical Trials in Oncology
Susan Halabi, Stefan Michiels in Textbook of Clinical Trials in Oncology, 2019
Recent advances in biotechnology, such as genome sequencing, have revolutionized the molecular oncology field and fostered the development of molecularly targeted agents that inhibit specific targeted molecules related to carcinogenesis and tumor growth. More recently, the role of the cancer abbreviations and immunogenic neoantigen generation has increasingly been appreciated, leading to the development of immune checkpoint inhibitors. At the same time, substantial molecular heterogeneity has been identified within histologically defined cancers. All of these new perspectives on cancer biology are expected to be utilized for the development of personalized or precision medicine. Indeed, the methodologies of clinical trials in oncology are in the midst of an evolution that is accelerating the realization of precision medicine [1].
What’s next in cancer immunotherapy? - The promise and challenges of neoantigen vaccination
Published in OncoImmunology, 2022
Alec J. Redwood, Ian M. Dick, Jenette Creaney, Bruce W. S. Robinson
The mutational landscape of a tumor is not homogenous55 meaning that genomic or proteomic neoantigen identification from a single biopsy is likely to be subject to sampling bias. This represents a potential barrier for successful neoantigen vaccination because vaccines that target poorly represented, sub-clonal, neoantigens could drive tumor escape through the process of immunoediting.56 Therefore, neoantigen vaccines would ideally consist of clonal neoantigens, i.e., those that arose early in the tumorigenesis and are expressed by the majority of cells. Sampling bias will affect the identification of clonal antigens meaning that multiple samples may need to be taken from each patient.57,58 This places significant logistical limits on neoantigen prediction and others have sought to use computational approaches for the identification of clonal neoantigens.59
Poly-ADP-ribose polymerases (PARPs) as a therapeutic target in the treatment of selected cancers
Published in Expert Opinion on Therapeutic Targets, 2019
Jarosław Przybycinski, Magdalena Nalewajska, Małgorzata Marchelek-Mysliwiec, Violetta Dziedziejko, Andrzej Pawlik
The immunotolerance to cancer cells in tumor microenvironments is a well-known pathological process that facilitates cancer growth and metastatic potential. There is a growing effort to reverse this phenomenon. Currently, large sets experimental data bind such hopes with checkpoint inhibitors that target CTLA4, PD-1 and PD-L1. There are already promising results from animal ovarian cancer models that suggest survival benefits from the combination of olaparib with CTLA4 antagonists. Another trial pointed out the immunomodulatory function of talazoparib, which increases CD8 and NK cell numbers in tumor microenvironments. Other trials covering this problem are underway [96]. In bladder cancer, two stage II trials have evaluated the effect of durvalumab (an antibody targeting PD-L1) combined with olaparib. The rationale of this combination lies in the immunogenic potential of DDR gene dysfunctions. The accumulation of DNA damage causes neoantigen generation in tumor cells. Interestingly, one PARPi resistance mechanism results from the overexpression of PD-L1 by cancer cells. Nonetheless, the effect of this synergistic combination on cancer stem cells is uncertain and needs further evaluation [104,107,108].
Generation of GM-CSF-producing antigen-presenting cells that induce a cytotoxic T cell-mediated antitumor response
Published in OncoImmunology, 2020
Hiroaki Mashima, Rong Zhang, Tsuyoshi Kobayashi, Yuichiro Hagiya, Hirotake Tsukamoto, Tianyi Liu, Tatsuaki Iwama, Masateru Yamamoto, Chiahsuan Lin, Ryusuke Nakatsuka, Yuta Mishima, Noriko Watanabe, Takashi Yamada, Satoru Senju, Shin Kaneko, Alimjan Idiris, Tetsuya Nakatsura, Hideki Ohdan, Yasushi Uemura
Next, we evaluated the treatment efficacy in an ICI-responsive tumor model (MC38 colon cancer).33 MC38 cells express a mutated ADP-dependent glucokinase (mAdpgk) with a single amino acid mutation.34 This mutation-derived cancer neoantigen is a promising target for cancer immunotherapy as such neoantigens are expressed only in cancer cells and not in normal cells.35,36 Although the wild type Adpgk (wtAdpgk) peptide-loaded GM-pMC vaccine showed no antitumor effect, the mAdpgk peptide-loaded GM-pMC vaccine significantly prolonged survival compared with that observed in the wtAdpgk peptide-loaded GM-pMC vaccine (Figure 10a-c). Moreover, in combination with ICI treatment, survival was significantly prolonged compare to that exhibited by the mAdpgk peptide-loaded GM-pMC vaccine alone. However, the benefit of the combination therapy was not remarkable as ICIs alone sufficiently suppressed this ICIs-responsive tumor.
Related Knowledge Centers
- Cancer Immunology
- Protein
- Neoplasm
- Cancer
- Antigen
- Cell
- Immune Response
- Host
- Tumor Marker
- Medical Test