New Breakthrough Report Reaffirms Proton Therapy Efficacy

A staggering 99% of prostate cancer patients treated with proton therapy believe they made the best treatment decisions for themselves, according to a new report released today at the National Proton Conference in Washington, D.C. The report analyzed outcomes and satisfaction of approximately 6,400 prostate cancer patients, more than 80% of whom received treatment at Loma Linda University Medical Center’s (LLUMC) James M. Slater Proton Treatment and Research Center.

“This report reaffirms the results we’ve seen from our patients for the past 22 years and supports the mountain of evidence regarding the efficacy of proton therapy,” said Jerry D. Slater, M.D., chairman of the LLUMC center. Dr. Slater and Dr. David A. Bush, vice-chairman of the department of radiation at LLUMC, recently co-authored a similar study entitled “Multi-Institutional Patient-Reported Quality of Life After Proton Therapy for Prostate Cancer Compared to Non-Treated Men.”

The just-released report was commissioned by the National Association for Proton Therapy (NAPT) and conducted by Dobson DaVanzo & Associates, LLC, an independent health economics and policy consulting firm. It looked at patient-based outcomes analysis and included personal questions that provided meaningful data that helps physicians make treatment decisions.

Not only did approximately 99% of the patients surveyed believe they made the best treatment decision for themselves, but an almost equal number – almost 98% – reported that they had recommended proton therapy to others.

Additional key findings of the report included:

  • Approximately 96% of patients were • satisfied or extremely satisfied with proton therapy.
  • Ninety-two percent of patients • reported that their quality of life was better or the same today than it was before their treatment. Only 8% stated that their quality of life was worse.
  • Ninety-two percent of respondents • reported that physical health or emotional problems did not interfere, or interfered very little, with their social activities.
  • Those who completed proton therapy • for the treatment of prostate cancer had similar urinary, bowel and hormonal health-related quality-of-life (HRQOL) measures compared to healthy individuals. For patients who received hormone therapy in addition to proton therapy, lower sexual HRQOL measures were reported. However, when looking at patients who received only proton therapy for the treatment of prostate cancer and who did not receive hormone or photon therapy, proton therapy patients reported lower HRQOL than healthy individuals in only one category, “sexual bother,” which refers to annoyance related to their sexual symptoms.

In addition to prostate cancer, proton therapy is effectively used to treat many different types of cancer. The outcomes of the NAPT report can be attributed to the pinpoint accuracy of the highly targeted proton beams. According to Dr. Slater, “Proton therapy is extremely effective as a treatment for prostate cancer because the targeted proton beams spare surrounding healthy tissue and minimize the typical side effects from standard photon beam radiation including incontinence and impotence.”

Since LLUMC introduced modern proton treatment for cancer into the mainstream in 1990, there have been countless studies and trials that have shown proton therapy to be the treatment of choice for many types of cancer. Over the years proton treatment has been refined and, coupled with leading-edge technology, has become one of the best treatment options for doctors and patients. While prostate cancer remains one of the primary uses for proton therapy, the pinpoint accuracy of the proton beam also makes it a highly effective form of treatment for many other types of tumors including those found in the head, neck, lung and breast.

Source: News Release.

Back to Phase 1: Understanding Systemic Effects of PV-10

The expression “bench to bedside” describes the progression from basic laboratory and animal research into disease and therapeutic processes through to “translational” studies that test human clinical applications suggested by those initial investigations. Sometimes, though, the arrow points the other way — “from bedside to bench,” for example, when promising clinical findings of apparent health benefits demand more granular and comprehensive understanding. That is the case in a Phase 1 study of a treatment for metastatic melanoma being conducted under Amod Sarnaik, MD, of the Experimental Therapeutics Program at the H. Lee Moffitt Cancer Center and a faculty member at the University of South Florida.

The therapy under investigation is intralesional PV-10 (Provectus Pharmaceuticals). PV-10 was developed from Rose Bengal, a xanthene dye combining halogens with fluorescein, patented in the 1880s. Before its antineoplastic potential was discovered and developed, it was used medicinally to fight eye infections, for staining, as an intravenous assay for impaired liver function, and as a food dye.

Back in October, 2012, Phase 2 metastatic melanoma data1 on use of intralesional PV-10 presented at ESMO (European Society for Medical Oncology) 2012 Congress in Vienna, Austria, showed an objective response rate (ORR) of 51%, and a disease control rate of 69% in target melanoma lesions. The other finding, which lies behind some of the intensifying interest in PV-10, was a 61% ORR in bystander (uninjected) lesions among patients who had complete or partial responses in their target lesions. The bystander lesion ORR in patients with nonresponsive target lesions was 18%. Of deep interest, as well, were case studies showing potential stasis or regression of untreated visceral lesions in patients following PV-10 treatment of their cutaneous lesions.

While PV-10 is known to be excluded from normal cells, it accumulates in the lysosomal membranes of cancer cells. There it subsequently triggers lysosomal release and complete autolysis of tumor cells relatively quickly–within 30-60 minutes of the injection. Importantly, this acute necrosis of the treated tumor does not appear to denature tumor antigens, potentially allowing acute exposure of antigenic tumor fragments to antigen-presenting cells.

Murine evidence

In murine research, Paul Toomey, MD, also of Moffitt, and colleagues used B16-F10 melanoma cells to establish a solitary subcutaneous flank tumor and multiple lung metastases in one study, and in a second study, bilateral flank tumors. When investigators administered a subcutaneous PV-10 injection to the flank tumor in the first study and a PV-10 injection in one of the tumors in the second, tumor size was reduced significantly. A bystander effect was clearly apparent in the first study in that PV-10-treated-mice had 3 or fewer lung metastases as compared with more than 250 in each of the untreated mice. Also, tumor-specific interferon (IFN)-? production was significantly higher (p 5 0.05) in the PV-10-treated mice. IFN-? is a cytokine that is critical for innate and adaptive immunity for tumor control. The overall conclusion, Dr. Toomey said, was that “intralesional PV-10 treatment leads to direct chemoablation of melanoma lesions and to a systemic response.”

Seeking an immune cell infiltrate

To find direct evidence of such a systemic immune response is part of the motive behind heading back to the bench—although this time involving human subjects. “A further impetus toward teasing out the precise mechanism of how PV-10 can exert a systemic immune response in patients,” said Dr. Sarnaik in an interview, “is to allow us to rationally combine PV-10 treatment with some of the exciting emerging immunotherapies for metastatic melanoma.”

The focus at Moffitt, Dr. Sarnaik continued, is on discerning the presence of immune cell infiltrate in untreated tumors after PV-10 injections into other lesions. “We are really interested in harnessing immune cell infiltrate as a form of treatment,” he said, noting also that while creating cancer vaccines has been thought of traditionally as one of the Holy Grails of cancer research, cancer vaccines have turned out to be not strong enough to generate an adequate immune response.

Adoptive cell transfer

The strategy of adoptive cell transfer potentially overcomes the weak vaccine response. With adoptive cell transfer, antigen-specific effector cells are taken from the patient’s tumor and expanded ex vivo under laboratory conditions favoring growth of T-lymphocytes and then re-infused to the patient. This precludes the need to provide antigens or to activate antigen-presenting cells.

In melanoma, T-cells from the tumor are cultured from tumor resection specimens in the presence of interleukin-2.A second strategy infuses peripheral blood T-cells that have been genetically engineered to express tumor-antigen-specific T-cell receptors2.

While adoptive cell transfer offers the advantage that enough T cells can be obtained for infusion in all patients, the T-cell receptors transfected into the T cells have a limited antigen-specificity. The strategy works, Dr. Sarnaik said, only about half the time. “We generate large numbers of T-lymphocytes, but we don’t have control over their quality. We think one of the limitations is that the T cells you get out of the tumor just aren’t good enough.” PV-10, however, does cause an immune response, suggesting that a combination treatment may improve the quality of the T-lymphocytes and have a greater impact on the disease.

When Shari Pilon-Thomas, PhD, also a Moffitt researcher, demonstrated that T-lymphocytes recovered from mice treated with PV-10 do appear to be of a higher quality, as evidenced by stronger tumor reactivity, the stage was set for Dr. Sarnaik’s current 15-patient pilot study. In it, one of two resectable melanoma tumors is injected with PV-10. Both are removed several weeks later. Serum is assessed before and after treatment to look for changes in the infiltration of immune cells. In patients with an immune response, PV-10 therapy can be continued.

“This is a straightforward study that will give a yes or no answer,” Dr. Sarnaik said.

Investigators will monitor carefully for known PV-10 adverse events, such as strong sun sensitivity, and interactions with diuretics, older psychiatric medications and some topical agents. Because drug concentrations are high only locally, intralesional therapy produces limited toxicities. The study will be completed in a year, with data analysis requiring another 6 months. First results may be ready in a year, however.

If the hypothesis that PV-10 will produce a better immune cell infiltrate is borne out, that would justify testing of combination treatments, Dr. Sarniak said. Likely candidates are adoptive cell therapy, approved drugs like ipilimumab that boost immune response, or PD-1-blocking antibodies (none approved yet).

What kind of therapy is PV-10?

Echoing Dr. Sarnaik, Eric Wachter, PhD, Provectus chief technology officer, said that he hopes that the findings of Dr. Sarnaik’s study will point toward rational judgments about combining PV-10 with other documented therapies. “We then might want to try two or more orthogonal therapies to stress tumor cells from several different angles simultaneously, for example an immune therapy plus a metabolic therapy (e.g., a kinase inhibitor), or in a rationally designed sequence.” In a hepatocellular carcinoma model, he added, PV-10 showed significant potential for synergy with 5-fluorouracil. Provectus recently initiated clinical testing of PV-10 with the multikinase inhibitor sorafenib, again bringing in two therapies with divergent mechanisms of action.

Which category does PV-10 fall into? “I think we are getting a clearer picture of how it might be classified, but it has features of several previously unrelated categories, such as of adoptive cell transfer and vaccination,” Dr. Wachter said. “PV-10 initially reduces tumor burden through chemoablation—but then activates the immune system bringing in capacities completely orthogonal to the ablative tumor destruction,” he added.

“Amod Sarnaik’s work may give us the molecular basis for closing the loop on one of the founding concepts for going into the clinic in the first place,” Dr. Wachter commented. “Back in the preclinical days at Provectus, Craig Dees, PhD, theorized that ablation of tumors with PV-10 might lead to unmasking of tumor antigenic material. I don’t think he anticipated that it would work as well as it does.”

Further testing

A Phase 3 randomized trial comparing PV-10 with dacarbazine and temozolomide monotherapy is expected to begin enrolling patients in Australia, the US and Europe later this year. The trial will include approximately 200 subjects with stage IIIB and IIIC melanoma and will have progression-free survival as its primary endpoint.

1) Sanjiv Agarwala, M.D., abstract #1137P, “Immuno-chemoablation of metastatic melanoma with intralesional rose bengal.”
2) W. Joost Lesterhuis and Cornelis J. A. Punt. “Harnessing the immune system to combat cancer.” 2012. Nature Reviews/Drug Discovery. Supplement to Nature Publishing Group Journals.

Synthetic Circuit Allows Dialing Gene
Expression Up or Down in Human Cells

Scientists who built a synthetic gene circuit that allowed for the precise tuning of a gene’s expression in yeast have now refined this new research tool to work in human cells, according to research published in the February 5, 2013 online issue of Nature Communications.

“Using this circuit, you can turn a gene from completely off to completely on and anywhere between those two extremes in each cell at once. It’s a nice tool if you want to know what happens at intermediate levels of gene expression. There has been no such system so far, but now it is available for mammalian cell research,” said senior author Gábor Balázsi, Ph.D., associate professor in The University of Texas MD Anderson Cancer Center Department of Systems Biology.

Present options for altering gene expression in human cells are blunt instruments by comparison. Knocking out a gene eliminates its expression completely. Inhibiting it with RNA interference dials it partially down and can affect other genes. Inserting a gene expression vector into cells overexpresses the gene, but it’s usually uncontrolled. Commercially available versions can switch a gene on or off, but cannot precisely dial between these extremes.

“For cancer research, the system will allow scientists to test the boundaries of a gene known to confer resistance to a drug in cancer cells by dialing its expression to different levels and treating the cells with the drug,” said first author Dmitry Nevozhay, M.D. Ph.D., instructor in Systems Biology.

“Likewise, such a system would allow personalized gene therapy, by precisely tuning the therapeutic gene level expression depending on disease progression and the patient’s need,” Nevozhay said.

In microbial or yeast biology research scientists have started to understand and manipulate gene function quantitatively, almost like we understand electronic circuits, Balázsi said. “This makes research in those areas more amenable to engineering and mathematical characterization, but that’s not true for human cells, and part of the problem is that tools that tune gene expression have been lacking.”

A step-by-step guide for others to build mammalian synthetic gene circuits

By refining their circuit to work in a human breast cancer cell line, the team demonstrated that their approach can be used in mammalian cells while offering a step-by-step guide that other researchers could follow to build other synthetic circuits for use with other genes.