Le, Son B.

Abstract Immune checkpoint inhibitors (ICIs) have limited benefit in recurrent high-grade astrocytoma (rHGA), largely because the blood–brain barrier and a profoundly immunosuppressive tumor microenvironment prevent T cells from infiltrating. Laser interstitial thermal therapy (LITT) is a minimally invasive, cytoreductive procedure that can “heat up” these otherwise “cold” tumors and sensitize them to ICIs. In this tri-institutional Phase 1/randomized Phase 2 trial (NCT02311582), bevacizumab- and immunotherapy-naïve rHGA patients were initially randomized 1:1 to either LITT followed by pembrolizumab (LITT+PEM) or non-LITT surgery (biopsy or resection) followed by pembrolizumab (NLS+PEM). Phase 2 participants enrolled at a second recurrence—with several already at a third recurrence—underscoring the advanced disease stage of this cohort. After 21 patients, randomization was halted when contemporaneous evidence showed limited benefit from adjuvant ICIs alone, and the remaining 24 patients received only LITT+PEM. In the 21-patient intent-to-treat cohort, LITT+PEM extended median OS to 21.3 months with 54% alive at 18 months (OS18) versus 6.7 months with 12.5% OS18 with NLS+PEM (HR 0.29; 95% CI, 0.01–0.88; p=0.021). Median PFS was 7.8 versus 2.2 months (HR 0.3; 95% CI, 0.10–0.87; p=0.020). Among 39 per-protocol patients, LITT+PEM yielded a median OS of 11.8 months with 42% OS18 versus 5.2 months with 0% OS18 for NLS+PEM (HR 0.17; 95% CI, 0.06–0.49; p=0.0002), and a median PFS of 4.5 versus 1.6 months (HR 0.21; 95% CI, 0.08–0.56; p=0.0006). The combination was well tolerated. Immune profiling revealed that LITT triggers early activation of non-classical monocytes—a change associated with improved survival—while subsequent pembrolizumab unleashes robust CD8⁺ T cell proliferation and clonal expansion. Long-term LITT+PEM survivors developed coordinated memory T-cell responses, whereas shorter-surviving patients exhibited stagnant memory pools and exhausted phenotypes. Together, these results demonstrate that LITT plus pembrolizumab is safe, overcomes rHGA’s immunosuppressive barrier, and mobilizes robust anti-tumor immunity.

Abstract The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.

Abstract Adaphostin (NSC 680410), an analog of the tyrphostin AG957, was previously shown to induce Bcr/abl down-regulation followed by loss of clonogenic survival in chronic myelogenous leukemia (CML) cell lines and clinical samples. Adaphostin demonstrated selectivity for CML myeloid progenitors in vitro and remained active in K562 cells selected for imatinib mesylate resistance. In the present study, the mechanism of action of adaphostin was investigated in greater detail in vitro. Initial studies demonstrated that adaphostin induced apoptosis in a variety of Bcr/abl- cells, including acute myelogenous leukemia (AML) blasts and cell lines as well as chronic lymphocytic leukemia (CLL) samples. Further study demonstrated that adaphostin caused intracellular peroxide production followed by DNA strand breaks and, in cells containing wild-type p53, a typical DNA damage response consisting of p53 phosphorylation and up-regulation. Importantly, the antioxidant N-acetylcysteine (NAC) blunted these events, whereas glutathione depletion with buthionine sulfoximine (BSO) augmented them. Collectively, these results not only outline a mechanism by which adaphostin can damage both myeloid and lymphoid leukemia cells, but also indicate that this novel agent might have a broader spectrum of activity than originally envisioned. (Blood. 2003;102:4512-4519)