Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial.

BACKGROUND: Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy. METHODS: We conducted a phase I trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x 5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing. RESULTS: Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n = 68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7-29.7) for DIPG. The subset of n = 26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p = 0.006) compared to n = 37 nonresponders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype. CONCLUSIONS: Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase II/III trials for pediatric brain tumors.

Mismatched Unrelated Donor Hematopoietic Stem Cell Transplantation Rescues Marrow Failure From Acute Leukemia Therapy in a Patient With Previously Undiagnosed Ligase IV Syndrome.

Patients with DNA double-strand breakage repair disorders are at increased risk of malignancy which is often difficult to treat given underlying sensitivity to chemotherapy and radiotherapy, lending an important role to hematopoietic stem cell transplantation. The choice of conditioning regimen used must balance reducing risk of rejection with minimizing excessive toxicity from myeloablative chemotherapy or ionizing radiation. We describe successful engraftment following a nonmyeloablative hematopoietic stem cell transplantation in a patient with Ligase IV syndrome and numerous pretransplant complications including malignancy, cardiac failure, and secondary hemophagocytic lymphohistiocytosis. Congruent with prior reports, a reduced intensity regimen appears efficacious in Ligase IV syndrome patients.

MERTK in cancer therapy: Targeting the receptor tyrosine kinase in tumor cells and the immune system.

The receptor tyrosine kinase MERTK is aberrantly expressed in numerous human malignancies, and is a novel target in cancer therapeutics. Physiologic roles of MERTK include regulation of tissue homeostasis and repair, innate immune control, and platelet aggregation. However, aberrant expression in a wide range of liquid and solid malignancies promotes neoplasia via growth factor independence, cell cycle progression, proliferation and tumor growth, resistance to apoptosis, and promotion of tumor metastases. Additionally, MERTK signaling contributes to an immunosuppressive tumor microenvironment via induction of an anti-inflammatory cytokine profile and regulation of the PD-1 axis, as well as regulation of macrophage, myeloid-derived suppressor cell, natural killer cell and T cell functions. Various MERTK-directed therapies are in preclinical development, and clinical trials are underway. In this review we discuss MERTK inhibition as an emerging strategy for cancer therapy, focusing on MERTK expression and function in neoplasia and its role in mediating resistance to cytotoxic and targeted therapies as well as in suppressing anti-tumor immunity. Additionally, we review preclinical and clinical pharmacological strategies to target MERTK.

Very late recurrence of B-cell acute lymphoblastic leukemia masquerading as a pituitary tumor.

Involvement of the pituitary gland by leukemic infiltration is exceedingly rare. Here, we describe a very late recurrence of B-cell acute lymphoblastic leukemia masquerading as a pituitary tumor and review the literature for previously reported cases. Our female patient presented 13 years after completion of therapy for B-ALL with headache, amenorrhea, galactorrhea and a pituitary mass. Subsequent studies revealed recurrence of her leukemia, and the pituitary lesion resolved after induction chemotherapy. Our case highlights the importance of considering leukemic infiltrate in the differential diagnosis of pituitary mass, particularly in a patient with a history of hematologic malignancy, sparing unnecessary surgical intervention and informing endocrine evaluation. In addition, the case also highlights difficulties with characterizing this recurrence as a very late relapse or clonal evolution of the original leukemia.

Acute spontaneous intracranial epidural haematoma and disseminated intravascular coagulation in a paediatric sickle cell patient.

An African American teenage boy during an acute sickle cell crisis spontaneously developed acute bifrontal epidural haematomas (EDHs) in addition to disseminated intravascular coagulation (DIC). The successfully evacuated EDH reaccumulated postoperatively. After multiple transfusions, the patient underwent repeat surgery. Subsequent maximal medical therapy was unable to significantly improve the patient's neurological status, and due to family wishes, care was withdrawn. EDH are the most common emergent neurosurgical complication of sickle cell disease (SCD). Twenty-two such cases have been previously reported. We present one further complicated by DIC leading to reaccumulation of the patient's EDH. An understanding of the mechanisms of EDH formation in SCD and their associated radiological findings could help clinicians identify when a patient is at high risk of EDH formation and thus offer the potential for early intervention prior to the development of an emergency.