Development of adaptive immune effector therapies in solid tumors

Abstract

State-of-the-art treatment strategies have drastically ameliorated the outcome of patients affected by cancer. However, resistant and recurrent solid tumors are generally nonresponsive to conventional therapies. A central factor in the sequence of events that lead to cancer is an alteration in antitumor immune surveillance, which results in failure to recognize and eliminate the transformed tumor cell. A greater understanding of the dysregulation and evasion of the immune system in the evolution and progression of cancer provides the basis for improved therapies. Targeted strategies, such as T-cell therapy, not only generally spare normal tissues, but also use alternative antineoplastic mechanisms that synergize with other therapeutics. Despite encouraging success in hematologic malignancies, adaptive cellular therapies for solid tumors face unique challenges because of the immunosuppressive tumor microenvironment, and the hurdle of T-cell trafficking within scarcely accessible tumor sites. This review provides a brief overview of current cellular therapeutic strategies for solid tumors, research carried out to increase efficacy and safety, and results from ongoing clinical trials.

Inhibition of TGF-β-receptor signaling augments the antitumor function of ROR1-specific CAR T-cells against triple-negative breast cancer

“…24 The use of SD-208 to block TGF-β-receptor signaling is also compatible with CAR T-cell products that target alternative antigens in TNBC, for example, mesothelin, B7-H3 and GD2, and may be combined with other strategies such as immune checkpoint blockade that are currently being investigated to augment the potency of CAR T-cell therapy. 25 Further, TGF-β-receptor signaling blockade may be applied to augment CAR T-cell potency in other cancer entities that have been demonstrated to produce TGF-β, eg pancreatic, esophageal, stomach, colon and prostate cancers. 26 Open access…”

Graft-versus-cancereffect and innovative approaches in the treatment of refractory solid tumors

“…However, some promising results have also been reported in some early phase studies [91]. Phase 1 studies of GD2-specific CAR-T cells for neuroblastoma, CAR-T cells specifically targeting HER2, EGFR and IL-13 for glioblastoma multiforme, mesothelin-specific CAR-T cells for advanced malignant pleural mesothelioma or pancreatic cancer, CAR-T cells specific for epidermal growth factor receptor (EGFR) for advanced nonsmallcell lung cancer and cholangiocarcinoma, CEA specific CAR-T cells for metastatic CRC have reported positive initial results [92][93][94][95][96][97][98][99].…”

“…The infiltration of the tumor tissue with T cells targeting tumor associated antigens has been shown to be associated with a favorable prognosis in several solid tumors. Upon this observation ongoing studies have been investigating the idea of extraction, ex vivo expansion with homeostatic cytokines and reinfusion into the patients as a novel treatment strategy [91]. Tumor infiltrating lymphocytes (TILs) were first reported by Rosenberg et al in 1988 and they demonstrated the antimelanoma effects of IL-2 induced TILs [100].…”

“…Despite the demonstration of TILs in other solid tumors, their expansion and in vivo efficacy have not been a great success as in melanoma [101]. However, there are promising preliminary data with cholangiocarcinoma and cervical cancer [105,106] and some clinical trials in gastrointestinal, gynecological, head and neck, breast and lung cancers are currently ongoing [91].…”

Prevention and Treatment of Tumor Lysis Syndrome in the Era of Onco-Nephrology Progress

“…Keeping in mind the crucial role of preserved renal function, it is logical that renal dysfunction/involvement automatically upgrades the risk category. Therapy-Related Factors During the last twenty years, particularly the last decade, the expanding knowledge of cancer immune evasion mechanisms and host-tumor interactions has significantly changed our therapeutic strategies in hemato-oncology [21][22][23][24][25]. Several novel targeted molecular and immune cell-based agents are now available, usually to be used in combination with conventional cytotoxic agents [26].…”