Left out in the cold: Moving beyond hormonal therapy for the treatment of immunologically cold prostate cancer with CAR T cell immunotherapies.

Prostate cancer is primarily hormone-dependent, and medical treatments have focused on inhibiting androgen biosynthesis or signaling through various approaches. Despite significant advances with the introduction of androgen receptor signalling inhibitors (ARSIs), patients continue to progress to castration-resistant prostate cancer (CRPC), highlighting the need for targeted therapies that extend beyond hormonal blockade. Chimeric Antigen Receptor (CAR) T cells and other engineered immune cells represent a new generation of adoptive cellular therapies. While these therapies have significantly enhanced outcomes for patients with hematological malignancies, ongoing research is exploring the broader use of CAR T therapy in solid tumors, including advanced prostate cancer. In general, CAR T cell therapies are less effective against solid cancers with the immunosuppressive tumor microenvironment hindering T cell infiltration, activation and cytotoxicity following antigen recognition. In addition, inherent tumor heterogeneity exists in patients with advanced prostate cancer that may prevent durable therapeutic responses using single-target agents. These barriers must be overcome to inform clinical trial design and improve treatment efficacy. In this review, we discuss the innovative and rationally designed strategies under investigation to improve the clinical translation of cellular immunotherapy in prostate cancer and maximise therapeutic outcomes for these patients.

Low-dose carboplatin modifies the tumor microenvironment to augment CAR T cell efficacy in human prostate cancer models.

Chimeric antigen receptor (CAR) T cells have transformed the treatment landscape for hematological malignancies. However, CAR T cells are less efficient against solid tumors, largely due to poor infiltration resulting from the immunosuppressive nature of the tumor microenvironment (TME). Here, we assessed the efficacy of Lewis Y antigen (LeY)-specific CAR T cells in patient-derived xenograft (PDX) models of prostate cancer. In vitro, LeY CAR T cells directly killed organoids derived from androgen receptor (AR)-positive or AR-null PDXs. In vivo, although LeY CAR T cells alone did not reduce tumor growth, a single prior dose of carboplatin reduced tumor burden. Carboplatin had a pro-inflammatory effect on the TME that facilitated early and durable CAR T cell infiltration, including an altered cancer-associated fibroblast phenotype, enhanced extracellular matrix degradation and re-oriented M1 macrophage differentiation. In a PDX less sensitive to carboplatin, CAR T cell infiltration was dampened; however, a reduction in tumor burden was still observed with increased T cell activation. These findings indicate that carboplatin improves the efficacy of CAR T cell treatment, with the extent of the response dependent on changes induced within the TME.

Disturbances in the performance of thermal discrimination tasks following cortical ablations in rats.

Previous studies of the effects of ablating the rat's somatosensory cortex on temperature discrimination have yielded negative results. Presently, it was assumed that (1) the rat's face might possess thermal acuity comparable to that found in highly sensitive skin regions of primates, (2) the rat's facial discriminative capacity for thermal differences might be more acute in a cool range well below normal room temperature (24 degrees C), and (3) by using more sensitive procedures and focusing on the effects of damage to the face areas in the rat's somatosensory cortex, disturbances in the capacity to make discriminations between cool stimuli might be revealed that previously went unnoticed. Results of experiments testing these assumptions indicated that rats can use their snouts to make discriminations of 1 degree C or less, that their acuity is better in the cool than in the warm range, and that somatosensory ablations produce moderate to severe disturbances in the capacity to discriminate between cool stimuli but only slight transitory disturbances in this capacity for warm stimuli. Additionally, the results suggest that the sensorimotor cortex may be involved in the rat's thermal discriminative capacity.

An experimental investigation of the parietal lobes and temperature discrimination in monkeys.

Seven groups of 3 monkeys each were given preoperative training over a series of thermal discrimination tasks of increasing difficulty to use eventually their left hands to detect a 1 degree C difference. One group served as an unoperated control (C), and the others were subjected to the following lesions: bilateral SI-bilateral SII; bilateral SI; bilateral SI-contralateral SII; bilateral SII-bilateral posterior parietal; bilateral parietal lobectomy; and contralateral parietal lobectomy. The groups were then tested again on the same tasks. No group showed any difficulty with differences larger than 12 degrees C, and groups 2, 4, 6 and C showed no statistical differences in their preoperative and postoperative number of trials to criteria for any of the temperature tasks. However, groups 1, 3 and 5 had considerable difficulty making discriminations ranging between 3 and 12 degrees C; and, although their postoperative performances were not significantly different from one another, they took statistically more trials to discriminate the 1 degree C difference in post- than in preoperative testing. Following extensive retraining, all but one of the subjects in the latter groups were able to detect the 1 degree C difference. It was concluded that the bilateral SI and contralateral SII areas play important roles in the monkey's ability to discriminate fine temperature differences with its hand, but that these areas are not essential to this capacity. It was also concluded that the monkey's parietal cortex plays little or no role in perceiving and reacting to noxious thermal stimulation applied to the hand.