New Clinical Trials: The Power of Research

An announcement earlier this month by the California Institute for Regenerative Medicine (CIRM), the state’s stem cell agency, is big news for innovative cancer treatment and the BCRF is right in the mix!

The Sanford Stem Cell Clinical Center at UC San Diego Health System, which is led by Lawrence Goldstein, PhD, and Catriona Jamieson, MD, PhD, was named one of three new “alpha clinics” by CIRM. Dr. Jamieson is the principal investigator on the alpha grant and co-leader of the Moores Cancer Center Hematologic Malignancies program. This designation comes with an $8 million award which will help provide vital infrastructure for establishing a comprehensive regenerative medicine clinical hub for first-in-human stem cell-related clinical trials including cancer treatment.

Recently, the Sanford Center launched three such trials including a Phase I trial to assess the safety and efficacy of a new monoclonal antibody for patients with chronic lymphocytic leukemia (CLL). The drug, called cirmtuzumab,was developed at Moores Cancer Center in the laboratory of Thomas Kipps, MD, PhD, co-leader of the Moores Cancer Center Hematologic Malignancies program. 

http://health.ucsd.edu/news/releases/Pages/2014-10-20-human-stem-cell-trials-at-UCSD.aspx

Want Is Immunotherapy?

The concept of ‘teaching’ the immune system to recognize and destroy cancer cells is over a century old, but the development of immunotherapeutic strategies for cancer was slow for many decades. However, much has been learned about the immune system in the meantime, and with the recent approval of two new immunotherapeutic anticancer drugs and several drugs in late-stage development, a new era in anticancer immunotherapy is beginning.

The video takes an audio-visual journey through the different approaches that are being investigated to harness the immune system to treat cancer. CLICK HERE

IMMUNO

Understanding ROR1

ROR1, an oncogene recently discovered on chronic lymphocytic leukemia (CLL) B cells, is being studied by researchers as a potential target for CLL treatment. Dr. Brian Koffman met with Dr. Thomas Kipps, who is researching ROR1, at the 2014 American Society of Clinical Oncology (ASCO) meeting to discuss this oncogene and its potential use in treating CLL.

Click HERE: https://www.youtube.com/watch?v=Zji6Fux_WGo

Thanks to Patient Power!fig1

 

Hitting a CLL Treatment “Home Run”

As more chronic lymphocytic leukemia CLL treatments are approved, with many more in development, are researchers closer to hitting a “home run” in treating the disease? Patient advocate Dr. Brian Koffman met with CLL expert Dr. Thomas Kipps at ASCO 2014 to explore emerging therapies and the goal for patients to achieve deep remission.

Click here:  https://www.youtube.com/watch?v=CYS78SbXjKAHome run

Thanks to Patient Power!

PCR duplicates in deep sequencing experiments and potential biasing

Published on the August 7th (2014) in the journal of Genome Biology:

Accurate allele frequencies are important for measuring subclonal heterogeneity and
clonal evolution. Deep-targeted sequencing data can contain PCR duplicates, inflating perceived read depth. Here we adapted the Illumina TruSeq Custom Amplicon kit to include single molecule tagging (SMT) and show that SMT-identified duplicates arise from PCR. We demonstrate that retention of PCR duplicate reads can imply clonal evolution when none exists, while their removal effectively controls the false positivhiseqe rate. Additionally, PCR duplicates alter estimates of subclonal heterogeneity in tumor samples. Our method simplifies PCR duplicate identification and emphasizes their removal in studies of tumor heterogeneity and clonal evolution.

For more details click here

Lenalidomide inhibits the proliferation of chronic lymphocytic leukemia cells via a cereblon/p21WAF1/Cip1-dependent mechanism independent of functional p53.

Lenalidomide has demonstrated clinical activity in patients with chronic lymphocytic leukemia (CLL), even though it is not cytotoxic for primary CLL cells in vitro. We examined the direct effect of lenalidomide on CLL-cell proliferation induced by CD154-expressing accessory cells in media containing interleukin (IL)-4 and IL-10. Treatment with lenalidomide significantly inhibited CLL-cell proliferation, an effect that was associated with the p53-independent upregulation of the cyclin-dependent kinase inhibitor p21WAF1/Cip1 (p21). Silencing p21 with small interfering RNA (siRNA) impaired the capacity of lenalidomide to inhibit CLL-cell proliferation. Silencing cereblon (CRBN), a known molecular target of lenalidomide, impaired the capacity of lenalidomide to induce expression of p21, inhibit CD154-induced CLL-cell proliferation, or enhance the degradation of Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3).

We isolated CLL cells from the blood of patients before and after short-term treatment with low-dose lenalidomide (5 mg per day) and found the leukemia cells also were induced to express p21 in vivo. These results indicate that lenalidomide can directly inhibit proliferation of CLL cells in a CRBN/p21-dependent, but p53-independent, manner at concentrations achievable in vivo, potentially contributing to the capacity of this drug to inhibit disease-progression in patients with CLL.

MicroRNA-155 influences CLL

MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia. High-level leukemia-cell expression of miR-155 is associated with more aggressive disease in patients with chronic lymphocytic leukemia (CLL), including those cases with low-level expression of zeta-chain associated protein of 70 kD (ZAP-70). CLL with high-level miR-155 expressed lower levels of Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1) and were more responsive to B-cell-receptor (BCR) ligation than CLLwith low-level miR-155.

Click Here for more information about the recently published article in the journal, Blood.

 

Prolonged lymphocytosis during Ibrutinib therapy

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has outstanding activity in patients with chronic lymphocytic leukemia. Most patients experience lymphocytosis, representing lymphocyte egress from nodal compartments.

This resolves within 8 months in the majority of patients, but a subgroup has lymphocytosis lasting >12 months. Here we report a detailed characterization of patients with persistent lymphocytosis during ibrutinib therapy. Signaling evaluation showed that while BTK is inhibited, downstream mediators of B-cell receptor (BCR) signaling are activated in persistent lymphocytes. These cells cannot be stimulated through the BCR and do not show evidence of target gene activation.

Progression-free survival is not inferior for patients with prolonged lymphocytosis vs those with traditional responses. Thus, prolonged lymphocytosis is common following ibrutinib treatment, likely represents the persistence of a quiescent clone, and does not predict a subgroup of patients likely to relapse early.

For more information: CLICK HERE