Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers.

BACKGROUND: Vaccination of cancer patients with p53-expressing modified vaccinia Ankara virus (p53MVA) has shown in our previous studies to activate p53-reactive T cells in peripheral blood but without immediate clinical benefit. We hypothesized that the immunological responses to p53MVA vaccine may require additional immune checkpoint blockade to achieve clinically beneficial levels. We therefore conducted a phase I trial evaluating the combination of p53MVA and pembrolizumab (anti-PD-1) in patients with advanced solid tumors. PATIENTS AND METHODS: Eleven patients with advanced breast, pancreatic, hepatocellular, or head and neck cancer received up to 3 triweekly vaccines in combination with pembrolizumab given concurrently and thereafter, alone at 3-week intervals until disease progression. The patients were assessed for toxicity and clinical response. Correlative studies analyzed p53-reactive T cells and profile of immune function gene expression. RESULTS: We observed clinical responses in 3/11 patients who remained with stable disease for 30, 32, and 49 weeks. Two of these patients showed increased frequencies and persistence of p53-reactive CD8+ T cells and elevation of expression of multiple immune response genes. Borderline or undetectable p53-specific T cell responses in 7/11 patients were related to no immediate clinical benefit. The first study patient had a grade 5 fatal myocarditis. After the study was amended for enhanced cardiac monitoring, no additional cardiac toxicities were noted. CONCLUSION: We have shown that the combination of p53MVA vaccine with pembrolizumab is feasible, safe, and may offer clinical benefit in select group of patients that should be identified through further studies.

Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.

Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.

Xeroderma pigmentosum: the role of phototesting.

We report three patients newly diagnosed as having xeroderma pigmentosum (XP). Previous photobiological studies have implicated ultraviolet (UV) B as the activating waveband in XP, causing a delayed and prolonged erythemal response. This characteristic reaction pattern has been used as a quick screening test in patients suspected of having XP, while awaiting confirmatory DNA repair studies. Two of our patients showed no abnormal erythemal responses, and one showed severe photosensitivity from 330 to 400 nm but normal UVB responses, with a peak erythema at 24 h. We conclude that the erythemal responses in XP are highly variable and cannot be considered as a reliable screening test in the diagnosis of XP.

Heat shock protein 70 induced during tumor cell killing induces Th1 cytokines and targets immature dendritic cell precursors to enhance antigen uptake.

Previously, we reported that killing tumor cells in vivo with the HSV thymidine kinase/ganciclovir system generates potent antitumor immunity, determined in part by the mechanism by which the cells die and by the levels of inducible heat shock protein (hsp) expression induced during the process of cell death. Here, we show that induction of hsp70 expression induces an infiltrate of T cells, macrophages, and predominantly dendritic cells (DCs) into the tumors as well as an intratumoral profile of Th1 cytokine expression (IFN-gamma, TNF-alpha, and IL-12) and enhances immunogenicity via a T cell-mediated mechanism. In addition, the protection conferred by hsp70 is both tumor and cell specific. We also demonstrate that hsp70 targets immature APC to make them significantly more able to capture Ags. This is likely to optimize cross-priming of the infiltrating APC with tumor Ags, which are simultaneously being released by the dying cells. In addition, using an Myc epitope-tagged hsp70 expression vector, we present evidence that hsp70 released from dying tumor cells is taken up directly into DCs and may, therefore, be involved in direct chaperoning of Ags into DCs. Taken together, our data suggest that hsp70 induction serves to signal the immune system of the presence of an immunologically relevant (dangerous) situation against which an immune reaction should be raised.

Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression.

In situ killing of tumor cells using suicide gene transfer to generate death by a non-apoptotic pathway was associated with high immunogenicity and induction of heat shock protein (hsp) expression. In contrast, a syngeneic colorectal tumor line, CMT93, killed predominantly by apoptosis, showed low levels of hsp expression and less immunogenicity. When apoptosis was inhibited in CMT93 cells by overexpression of bcl-2, hsp was also induced. Furthermore, when cDNA encoding hsp70 was stably transfected into B16 and CMT93 cells, its expression significantly enhanced the immunogenicity of both tumors. Increased levels of hsp, induced by non-apoptotic cell killing, may provide an immunostimulatory signal in vivo which helps break tolerance to tumor antigens. These findings have important implications for the development of novel anti-cancer therapies aimed at promoting patients' immune responses to their own tumors.

Staphylococcal scalded skin syndrome in an adult. Influence of immune and renal factors.

We report a case of staphylococcal scalded skin syndrome in a 77-year-old man with an infected surgical wound. The patient was immunocompetent and had only mildly impaired renal function. The pathogenic and aetiological factors of the condition are discussed.

Superficial granulomatous pyoderma. A report of two cases.

We report two cases of superficial granulomatous pyoderma (SGP). Unlike classical pyoderma gangrenosum this variant is characterized by a benign course, superficial ulceration and a granulomatous infiltrate. Although our cases share the typical features of SGP, they are noteworthy in that one had the disease for 18 years, and the other had concomitant sarcoidosis.

Can dyslexia be treated? Treatment-specific and generalized treatment effects in dyslexic children's response to remediation.

A total of 178 reading disabled children were randomly assigned to one of three treatment conditions providing training in word recognition and decoding skills (DS), oral and written language (OWLS), or classroom survival skills (CSS. an alternative treatment control). Pre- and post-treatment comparisons on an array of standardized and experimental measures indicated that the two experimental treatments (DS, OWLS) resulted in improvement on selected tests significantly greater than that resulting from a third treatment intervention which controlled for treatment time and individual attention (CSS). Effects specific to each experimental treatment were identified, as well as some generalized treatment advantages shared by both experimental groups at post-test. These results indicate that some of the deficits associated with developmental dyslexia are amenable to treatment. Greater generalization of treatment effects was observed following the DS than the OWLS treatment. While DS-instructed children exhibited better word recognition skills, however, their knowledge of grapheme-phoneme correspondence rules was not improved. Several OWLS-specific effects observed on experimental reading and language measures were not replicated on standardized tests which purport to measure the same skills. These results are discussed with respect to (i) possible mechanisms by which disabled readers may acquire word recognition skills, (ii) their failure to acquire and use grapheme-phoneme correspondence rules, and (iii) a possible reduced tendency in the present population to generalize newly acquired specific knowledge to related knowledge domains.

Exogenous ochronosis: an epidemiological study.

A survey was conducted to investigate the relationship between exogenous ochronosis and the use of skin lightening preparations amongst black individuals attending general outpatient departments in two South African hospitals. In the sample, 15% of males and 42% of females were found to have exogenous ochronosis. The prevalence amongst users of skin lighteners was 69%. The main demographic associations with ochronosis were an inverse relationship to education, and predominance of the female sex. Clinical and behavioural aspects were also recorded. Even products limited to 2% hydroquinone or less, and combined with a sunscreen, were found to cause ochronosis.

Patterns of dermatology referrals in a general hospital.

A survey of 500 patients hospitalized in non-dermatology wards and referred for dermatological opinion is reported. In approximately 50%, the skin lesions were related to the presenting illness; in 36.6% of these patients the skin condition contributed substantially to the diagnosis of the systemic disease. This study emphasizes the considerable interface between cutaneous and systemic disease and the need for close co-operation between medical and dermatology departments. The implications for postgraduate education are highlighted, since such patients are infrequently seen in a dermatology out-patient setting.