The past decade has seen tremendous advances in both our understanding of cancer immunosuppressive microenvironments and colonic bacteria facilitated by immune checkpoint inhibitor antibodies and next generation sequencing, respectively. Because an important role of the host immune system is to communicate with and regulate the gut microbial community, it should not come as a surprise that the behavior of one is coupled to the other. In this review, we will attempt to dissect some of the studies demonstrating cancer immunotherapy modulation by specific gut microbes and discuss possible molecular mechanisms for this effect.

Overcoming the leukemia stem cell resistance to intensive chemotherapy has been an area of extensive research over the last two decades. Advances and greater understanding of the molecular biology of leukemia stem cells are in rapid progress. Targeted therapies are currently being used in clinical practice with reasonable response rates, but a cure is being achieved in only a small percentage of patients, most likely due to tumor mutational heterogeneity. A genetically engineered diphtheria toxin fused with interleukin-3 (SL-401 or tagraxofusp) has shown robust activity in blastic plasmacytoid dendritic cell neoplasm and promising response rates in different myeloid malignancies, including eradication of minimal residual disease. Multiple clinical trials are being conducted using this drug and the preliminary results are encouraging. This article reviews the clinical trials for SL-401, its mechanism of action, clinical activity, and the adverse event profile.

191 Background: For 10-15% of cancer patients, pain cannot be controlled using existing therapies (Zech et al., Pain, 63, 65-76, 1995). SP-SAP is the first targeted toxin to undergo phase I testing for pain. SP-SAP (Wiley and Lappi, Neurosci Lett, 230, 97-100, 1997) covalently linkes substance P (SP), a neuromodulator that binds to NK1 receptors on laminae I and X of the dorsal horn, and saporin (SAP), a ribosomal toxin that ablates cells that express NK1 and endocytose the toxin. Intrathecal injections of SP-SAP in rats reduce chemically or thermally induced pain, thermal hyperalgesia, and mechanical allodynia, with no signs of motor, sensory, or behavioral dysfunction (Mantyh et al., Science, 278, 275-9, 1997; Nichols et al., Science, 286, 1558-61, 1999; Suzuki et al., Nature Neurosci, 5, 139-26, 2002; Vierck et al., Neurosci, 199, 223-32, 2003). In canines, intrathecal injections into the lumbar region – 45 mcg for 10-15 kg (Allen et al., Toxicol Sci, 91, 286-98, 2006) or 15 mcg for 8-12 kg (Wiese et al., Anesthesiol, 119, 1163-77, 2013) – produce no neurological, behavioral, or histological deficits. A double-blinded RCT of SP-SAP for the treatment of bone pain in canines (Brown and Agnello, Anesthesiol, 199, 1178-85, 2013) showed that a single injection of 60 mcg (above 30 kg) or 40 mcg (below 30 kg) significantly reduced pain as measured by time to owner unblinding (p=0.002) or number of canines unblended (p=0.001). Methods: A single intrathecal injection of SP-SAP is made at the L5-S1 interspace of cancer patients with intractable sub-umbilical pain. Single subject cohorts are at doses of 1, 2, 4, 8, 16, 32, 64, and 90 mcg. Primary outcomes are assessed by pain survey (VAS “bothersome pain”, VAS “pain intensity”, ODI, EQ-5D, and BDI) and medication use log. Patients are monitored for toxicity, neurological and cardiac abnormalities, and SP-SAP antibodies for 6 months. Results: This report presents the results from the first three subjects of the phase I study. No evidence of toxicity or neurological or cardiac abnormalities were found. No clear evidence for pain reduction was observed. Conclusions: At existing doses (< 4 mcg), SP-SAP appears safe for human use. The study is continuing with dose escalation. Clinical trial information: NCT02036281.