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How can chemoimmunotherapy best be used for the treatment of colon cancer? “Numerous immunotherapeutic approaches have been tested against colon carcinoma in a wide range of preclinical and clinical settings.” KEYWORDS: chemotherapy n colon cancer n immunotherapy
Immunity, inflammation & colon cancer The colon, as part of the intestine, is constantly exposed to a variety of nutrients and commensal bacteria. These exogenous stimuli shape the particular tissue-specific immune system in the colon. This system is rich in innate lymphoid cells, CD103 + dendritic cells, IgA-secreting plasma cells, Tregs and Th17 cells. This unique immune milieu is regulated by endogenous signals (e.g., TGF‑β) that work in concert with exogenous signals derived from bacteria, or nutrients such as retinoic acid derived from vitamin A, or aryl hydrocarbon receptor ligands present in some vegetables [1] . However, this subtle equilibrium between nutrients, microbiota and the colonic immune system can be unbalanced when a chronic inf lammatory process settles in the colon. Chronic inflammation is an enabling factor for the tumorigenic process [2] . Indeed, the colon is the organ that best reflects the link between chronic inflammation and cancer. Intestinal inflammatory disease is associated with an increase in cancer risk. Moreover, several studies have associated the prolonged uptake of antiinflammatory drugs with a reduced risk of colon cancer [3] .
tumor still preserves an immune infiltration rich in Th1-polarized and cytotoxic memory T cells, the patient has a better prognosis and chemotherapy can activate the endogenous immune response [4] . This is a frequent situation in colon cancer, which makes this cancer especially suitable for chemoimmunotherapy.
The result of the tumorigenic process in the context of chronic colonic inflammation is the promotion of colon cancer with an enriched stroma. The growing tumor constantly shapes the intratumoral immune response in order to promote tissue and vascular growth, imitating the stroma of a healing would. However, if the
Chemoimmunotherapy basics The progress achieved throughout the last decade in understanding the tumor stroma as a complex interacting network of cancer cells with various cell subsets opened the door to a new era of therapeutic interventions based on strengthening the host’s immune army to win the battle against cancer. Chemotherapeutics are known to kill tumor cells. However, preclinical and clinical data support their role in remodeling the tumor micro environment by, among other mechanisms, altering the innate and adaptive suppressive immune responses within the tumor towards antitumor immunity. For instance, oxaliplatin, which shows clinical activity in colorectal cancer, induces tumor cell death in a way that potently stimulates antitumor immune responses, known as immunogenic cell death [5] . The goal of immunotherapy in cancer is the modulation of the host immune system towards significant antitumor effects. These approaches include antitumor vaccines, therapeutic antibodies and immunostimulatory cytokines. Therapeutic vaccines are based on enhancing dendritic cell activation and antigen crosspriming, leading to strong adaptive immune responses. Indeed, the US FDA approved Sipuleucel‑T as the first vaccine for prostate cancer [6] . Immunostimulatory antibodies are designed to reverse immune tolerance and promote antitumor responses. Their efficacy is highly contrasted both in preclinical and clinical
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“Of extraordinary interest are the PD1‑targeted antibodies that are now in Phase III trials with excellent results for both safety and efficacy.”
José Medina-Echeverz
Division of Hepatology & Gene Therapy, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain
Pedro Berraondo
Author for correspondence: Division of Hepatology & Gene Therapy, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain
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settings. Cytokine therapy has proven to be very efficacious in animal models. Finding ways of modulating their potent action by combining cytokine usage with other anticancer agents is the subject of several clinical trials presently.
Chemoimmunotherapy in colon cancer Currently, numerous immunotherapeutic approaches have been tested against colon carcinoma in a wide range of preclinical and clinical settings. Regarding chemoimmunotherapy for this malignancy, several clinical trials have been run up to now. Most include combination chemotherapy of 5-fluorouracil, folinic acid and either irinotecan (FOLFIRI) or oxaliplatin (FOLFOX). Among others, cytokines such as IL‑2, GM-CSF or monoclonal antibodies against the EGF receptor or VEGF have been the preferred immunomodulatory agents to combine with the FOLFIRI and FOLFOX chemotherapeutic regimes [7–11] . Although the results are not as promising as desired, clinical research performed over the past few years has continued to shed light on the field. For instance, the density, position and abundance of different T cells and myeloid cell subsets in the tumor tissues of a patient prior to a therapeutic regime are being proven to have a clinical impact on the survival of those with colorectal cancer [12] . As cancers are as unique as humans, the immunological status of the patient will help in carrying out more effective clinical trials in the near future.
“The progress achieved throughout the last
decade ... opened the door to a new era of therapeutic interventions based on strengthening the host’s immune army to win the battle against cancer.” Meanwhile, preclinical efforts are focused on understanding the cooperative roles of chemotherapy and immunotherapy in remodeling tumor stroma towards antitumoral responses [13–15] . Regarding colon cancer, we have described how combining low-dose cyclophosphamide with IL‑12 immunotherapy alters established tumor microenvironments. This leads to a modification of tumor myeloid-suppressive cell subsets into inflammatory myeloid counterparts, which is crucial for the antitumor effect [16] . Moreover, delivery of IL‑12, combined with an oxaliplatin regime, diminishes tumor myeloid cell populations and boosts adaptive immune responses in a liver model of colorectal metastases [17] . 1788
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Conclusion Colon cancer is a common malignancy, frequently associated with chronic inflammation. Part of the inflammatory infiltrate in these tumors is composed of several types of immune cells. Indeed, the immune score is a good prognostic parameter in colon cancer. The adjuvant activity of chemotherapy can be boosted by modulating the endogenous immune response present in these tumors. This modulation can be achieved by combining immunostimulatory compounds and the appropriate doses and schedules of traditional chemotherapeutic drugs. In the near future, intense clinical research will translate the knowledge about chemoimmunotherapy acquired in mice into clinical practice, increasing the therapeutic arsenal used to fight colon cancer. Future perspective The basics of chemoimmunotherapy in animal models are well established. However, it is extremely difficult to transfer this knowledge into clinical practice as there are several hurdles that must be overcome. The most important obstacles for chemoimmunotherapy are: The marked differences between the immune system of mice and humans. Although the same principles operate both in humans and mice, a great research and development effort is required to gain an indepth insight into the mechanism of action of the successful chemo immunotherapies in mice. Then, the drugs that can achieve the same immunological outcome in humans will have to be identified. In some instances, the drugs will be the same as those used in mice, but in other cases, other related candidates will be more appropriate for human research; The synergy between chemotherapy and immunotherapy is often observed at a specific dose and time interval between both drugs. Subtle variations of the optimum protocol results in loss of synergy or even reduced therapeutic efficacy. Translating the optimal schedule to humans is an empirical task that requires an enormous investment that is not always available; Many of the tools in the immunotherapeutic arsenal will have no antitumor efficacy alone and will not be approved as a single agent. This fact limits the immunotherapeutic compounds that can be combined with approved chemotherapies. While the safety of the patients must remain as the first issue regarding clinical future science group
How can chemoimmunotherapy best be used for the treatment of colon cancer?
trials, it is advised that requirements must be flexible in order to perform combination trials, especially in those compounds where a therapeutic effect can only be expected when combined with chemotherapy [18] ; Traditional end points in cancer clinical trials should be revised to adjust to the particularities of immunotherapy where delayed responses and long-term stabilizations will be more frequent [19] . Therefore, the challenge is now to transfer the proofs-of-principle learnt in the animal models to humans. The recent approval of the anti-CTLA4 antibody ipilimumab will certainly boost this field since clinical trials of combined treatments of two approved and effective drugs will be easily performed [20] . In a few years, other potent immunotherapy compounds are expected to be approved and the arsenal available to combine with traditional chemotherapy will increase. Of extraordinary interest are the PD1-targeted antibodies that are now in Phase III trials with excellent results for both safety and efficacy [21] . The discovery of the doses and timing of traditional chemotherapies that maximize the immune response is another strategy that might boost chemotherapy in humans. The immunomodulatory properties of an old alkylating agent, cyclophosphamide, were described in mice over
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10 years ago [22] . However, it was not until this decade that the protocols that efficiently decrease Tregs in humans were established [23,24] . Finally, a clinical trial combining cyclophosphamide and an antitumor vaccine has recently been published that showed a clear improvement in the survival of patients treated with cyclophosphamide [25] . It is likely that many other drugs with immunomodulatory activities in mice will follow a similar process, which will result in the discovery of the therapeutic clinical protocol that elicits the endogenous antitumor immune response in patients. This process will be accelerated with the new anticancer drugs that inhibit enzymes involved in the development of tumors, since the immunomodulatory activities of these new drugs are evaluated in the early phases of the development process. Financial & competing interests disclosure J Medina-Echeverz was funded by a grant from the Spanish Fondo de Investigación Sanitaria. P Berraondo was funded by a Miguel Servet contract from the Spanish Fondo de Investigación Sanitaria. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Hamblin TJ, Inzani V, Sadullah S et al. A Phase-II trial of recombinant interleukin2 and 5FU chemotherapy in patients with metastatic colorectal carcinoma. Cancer Treat. Rev. 16(Suppl. A), S163–S167 (1989). Correale P, Cusi MG, Tsang KY et al. Chemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin2 induces strong immunologic and antitumor activity in metastatic colon cancer patients. J. Clin. Oncol. 23(35), 8950–8958 (2005). Gebbia V, Del Prete S, Borsellino N et al. Efficacy and safety of cetuximab/irinotecan in chemotherapy-refractory metastatic colorectal adenocarcinomas: a clinical practice setting, multicenter experience. Clin. Colorectal Cancer 5(6), 422–428 (2006).
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Pilot clinical trial of type 1 dendritic cells
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