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Purpose:Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system.Experimental Design:We developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models.Results:B7-H3 CAR T cells mediate significant antitumor activity in vivo, causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3.Conclusions:B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials.

Purpose: Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system. Experimental Design: We developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models. Results: B7-H3 CAR T cells mediate significant antitumor activity in vivo, causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3. Conclusions: B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials.

Faces and bodies are complex structures, perception of which can play important roles in person identification and inference of emotional state. Face representations have been explored using behavioural adaptation: in particular, studies have shown that face aftereffects show relatively broad tuning for viewpoint, consistent with origin in a high-level structural descriptor far removed from the retinal image. Our goals were to determine first, if body aftereffects also showed a degree of viewpoint invariance, and second if they also showed pose invariance, given that changes in pose create even more dramatic changes in the 2-D retinal image. We used a 3-D model of the human body to generate headless body images, whose parameters could be varied to generate different body forms, viewpoints, and poses. In the first experiment, subjects adapted to varying viewpoints of either slim or heavy bodies in a neutral stance, followed by test stimuli that were all front-facing. In the second experiment, we used the same front-facing bodies in neutral stance as test stimuli, but compared adaptation from bodies in the same neutral stance to adaptation with the same bodies in different poses. We found that body aftereffects were obtained over substantial viewpoint changes, with no significant decline in aftereffect magnitude with increasing viewpoint difference between adapting and test images. Aftereffects also showed transfer across one change in pose but not across another. We conclude that body representations may have more viewpoint invariance than faces, and demonstrate at least some transfer across pose, consistent with a high-level structural description.

The reading of text is predominantly a left hemisphere function. However, it is also possible to process text for attributes other than word or letter identity, such as style of font or handwriting. Anecdotal observations have suggested that processing the latter may involve the right hemisphere. We devised a test that, using the identical stimuli, required subjects first to match on the basis of word identity and second to match on the basis of script style. We presented two versions, one using various computer fonts, and the other using the handwriting of different individuals. We tested four subjects with unilateral lesions who had been well characterized by neuropsychological testing and structural and/or functional MRI. We found that two prosopagnosic subjects with right lateral fusiform damage eliminating the fusiform face area and likely the right visual word form area were impaired in completion times and/or accuracy when sorting for script style, but performed better when sorting for word identity. In contrast, one alexic subject with left fusiform damage showed normal accuracy for sorting by script style and normal or mildly elevated completion times for sorting by style, but markedly prolonged reading times for sorting by word identity. A prosopagnosic subject with right medial occipitotemporal damage sparing areas in the lateral fusiform gyrus performed well on both tasks. The contrast in the performance of patients with right versus left fusiform damage suggests an important distinction in hemispheric processing that reflects not the type of stimulus but the nature of processing required.

A recent study hypothesized a configurational anisotropy in the face inversion effect, with vertical relations more difficult to process. However, another difference in the stimuli of that report was that the vertical but not horizontal shifts lacked local spatial references. Difficulty processing long-range spatial relations might also be predicted from a relevance-interaction explanation, which proposes that in inverted faces, spatial relations are processed efficiently only within high-relevance local regions. The authors performed 2 experiments to distinguish between these hypotheses. Experiment 1 showed that the inversion effect for vertical shifts of the eyes alone was more similar to that for horizontal eye shifts than for vertical shifts of the eyes and eyebrows. In Experiment 2, focused attention reduced the inversion effect for vertical mouth position more than that for vertical shifts of the eyes and brows. The authors concluded that face inversion impairs the perception of both local spatial relations in low-relevance regions and long-range spatial relations extending across multiple facial regions, consistent with a loss of efficient whole-face processing of the spatial relations between features.

Case reports have suggested that perception of the eye region may be impaired more than that of other facial regions in acquired prosopagnosia. However, it is unclear how frequently this occurs, whether such impairments are specific to a certain anatomic subtype of prosopagnosia, and whether these impairments are related to changes in the scanning of faces. We studied a large cohort of 11 subjects with this rare disorder, who had a variety of occipitotemporal or anterior temporal lesions, both unilateral and bilateral. Lesions were characterized by functional and structural imaging. Subjects performed a perceptual discrimination test in which they had to discriminate changes in feature position, shape, or external contour. Test conditions were manipulated to stress focused or divided attention across the whole face. In a second experiment we recorded eye movements while subjects performed a face memory task. We found that greater impairment for eye processing was more typical of subjects with occipitotemporal lesions than those with anterior temporal lesions. This eye selectivity was evident for both eye position and shape, with no evidence of an upper/lower difference for external contour. A greater impairment for eye processing was more apparent under attentionally more demanding conditions. Despite these perceptual deficits, most subjects showed a normal tendency to scan the eyes more than the mouth. We conclude that occipitotemporal lesions are associated with a partially selective processing loss for eye information and that this deficit may be linked to loss of the right fusiform face area, which has been shown to have activity patterns that emphasize the eye region.

A word-length effect is often described in pure alexia, with reading time proportional to the number of letters in a word. Given the frequent association of right hemianopia with pure alexia, it is uncertain whether and how much of the word-length effect may be attributable to the hemifield loss. To isolate the contribution of the visual field defect, we simulated hemianopia in healthy subjects with a gaze-contingent paradigm during an eye-tracking experiment. We found a minimal word-length effect of 14 ms/letter for full-field viewing, which increased to 38 ms/letter in right hemianopia and to 31 ms/letter in left hemianopia. We found a correlation between mean reading time and the slope of the word-length effect in hemianopic conditions. The 95% upper prediction limits for the word-length effect were 51 ms/letter in subjects with full visual fields and 161 ms/letter with simulated right hemianopia. These limits, which can be considered diagnostic criteria for an alexic word-length effect, were consistent with the reading performance of six patients with diagnoses based independently on perimetric and imaging data: two patients with probable hemianopic dyslexia, and four with alexia and lesions of the left fusiform gyrus, two with and two without hemianopia. Two of these patients also showed reduction of the word-length effect over months, one with and one without a reading rehabilitation program. Our findings clarify the magnitude of the word-length effect that originates from hemianopia alone, and show that the criteria for a word-length effect indicative of alexia differ according to the degree of associated hemifield loss.

Written texts are not just words but complex multidimensional stimuli, including aspects such as case, font, and handwriting style, for example. Neuropsychological reports suggest that left fusiform lesions can impair the reading of text for word (lexical) content, being associated with alexia, whereas right-sided lesions may impair handwriting recognition. We used fMRI adaptation in 13 healthy participants to determine if repetition–suppression occurred for words but not handwriting in the left visual word form area (VWFA) and the reverse in the right fusiform gyrus. Contrary to these expectations, we found adaptation for handwriting but not for words in both the left VWFA and the right VWFA homologue. A trend to adaptation for words but not handwriting was seen only in the left middle temporal gyrus. An analysis of anterior and posterior subdivisions of the left VWFA also failed to show any adaptation for words. We conclude that the right and the left fusiform gyri show similar patterns of adaptation for handwriting, consistent with a predominantly perceptual contribution to text processing.