Cytokines comprise a category of signaling proteins, peptides, or glycoproteins that are used extensively in cellular communication. They include a large and diverse family of polypeptide regulators that are produced widely throughout the body by various types of cells. Interleukins are cytokines used to regulate inflammatory and immune responses by activating the body's white blood cells, such as T-lymphocytes (T cells). There are more than 20 known types of interleukins, with the clinical use of some having varying levels of success in the fight against cancer.
Interleukin-12 (IL-12) is largely produced by monocytes, macrophages, and dendritic cells in response to bacterial products such as lipopolysaccharide (LPS) and intracellular pathogens. It can induce IFN gamma production, cell proliferation, and cytotoxicity mediated by natural killer (NK) cells and T cells-all immune responses that can be used against not only the typical foreign invaders such as bacteria and viruses, but also cancer cells. However, its use as an anti-tumor agent must be carefully balanced as the toxicity of the IL-12 is well documented. Target organs affected include the lymphohematopoietic system, intestines, liver, and lungs; which necessitate careful administration technique and schedules. Due to recent events more fully validating increasingly promising use of IL-12, I thought it important to delve into some pharmaceutical companies that are evaluating its effectiveness in fighting cancer.
Ziopharm's Adenovirus-Delivered IL-12 gene Administration
Ziopharm Oncology (NASDAQ:ZIOP) has a growing pipeline of therapies being evaluated for treating various types of cancers. Its pipeline is heralded by palifosfamide, an alkylating chemotherapy drug designed to halt tumor growth by binding to cancer cell DNA and interfering with its function. Palifosfamide is in Phase III trials evaluating its effectiveness in treating extensive-stage small cell lung cancer (SCLC) and metastatic soft tissue sarcoma (STS).
However, the earlier stage IL-12 DNA program has been grabbing headlines recently as well. On October 25th the company announced Phase I data and Phase II initiation of Ad-RTS IL-12, a novel DNA-based therapeutic candidate to treat advanced melanoma. Phase I data of a 13-patient set indicated clinical response in 5 of 7 patients dosed at the higher dosage levels. In terms of safety, there were two related adverse events of note: pyrexia and cytopenia.
The Phase II trial initiation announced in the press release is expected to enroll 15 patients with unresectable (inoperable) stage 3 or 4 melanoma to further evaluate the safety and efficacy of intratumoral injections of Ad-RTS IL-12. A step beyond the older technology of merely injecting IL-12 cytokines into targeted tumors, Ad-RTS IL-12 employs the use of an adenoviral vector to deliver into the patients' cells a gene which causes the cells to produce IL-12. Termed the RheoSwitch Therapeutic System™ (RTS™), Ziopharm gained rights to the technology via a January 2011 agreement with the developer, Germany-based Intrexon Corporation.
In order to control the IL-12 expression, an inducible promoter is utilized, which is conditionally activated by an orally bioavailable small molecule activator ligand (L), RG115932. This controlled IL-12 expression causes a strong immune response directly against the cells having this expression. With a careful balancing act of injection amount and activator ligand, most of the adenovirus-delivered IL-12 gene is at the tumor site where the immune response should focus. Early in a Phase II trial, interim updates on this trial should be forthcoming and will give an indication of the efficacy and safety profile of the regimen.
Particularly interesting in the Phase I trial data was the observation that "An important early sign of this effect was manifested in lesions not injected with Ad-RTS IL-12, where clinical response was observed, indicating systemic, anti-cancer immune activity." This immune system response, if robust and long-term, could indicate a therapy which would not only treat the targeted melanoma (locally and systemically), but could also help prevent its recurrence.
The systemic response, seen in some successful immunotherapy agents used to fight cancer, is most likely the result of local dendritic cells and other antigen-presenting cells that were exposed to the dying cancer cell fragments when the cells were targeted by the immune stem as part of the initial treatment regimen. These cell fragments help to "teach" the immune system what the cancer cells "look" like and enable them to target the distant (not at injection site) melanoma cells as well.
Although much of Ziopharm's current $328 million market capitalization is attributed to palifosfamide, investors should certainly be watching for updates on Ad-RTS IL-12 in the coming months. The company's common shares are trading near their YTD lows with short-term support seen at $4.00, providing for good near-term entry for interested shareholders. Additional research is advised before opening a position in the company, with the company's most recent 10Q being an advisable next step.
OncoSec Medical's Electroporation Delivered IL-12 Gene
OncoSec Medical Inc (OTCQB:ONCS) has had an impressive year with many promising developments in its pipeline. The company's OncoSec Medical System (OMS) platform is based on an electroporation administration system it licensed from Inovio Pharmaceuticals (NYSEMKT:INO) in March of 2011. The license pertains to "certain non-DNA vaccine technology and intellectual property relating to electroporation technology useful for electrochemical and cytokine- based immune therapies for treating solid tumors." The OMS system is based on a unique physiological response cell membranes have when exposed to electrical stimulation. OncoSec's administration device is a 6-needle (actually 6-electrode) hand-held applicator that is used to apply a brief electrical current across the targeted tumors.
The current causes a significant increase in the permeability of the affected cells' membranes, which dramatically increases cellular uptake of a pre-injected agent (4,000 to 10,000-fold), thereby increasing the agent's effectiveness. Once the current is removed, the cell membranes return to their original states, trapping the incorporated agents inside. The administration is favorable due to not only the increased effectiveness of the agents by being quickly delivered to the cells' interiors where they work more effectively, but less of the agent is required to have the same level of efficacy-or the same amount of agent may be used with even greater efficacy. Just as important is the fact that the administration technique focuses on keeping the agents in a centralized area rather than allowing the often toxic agents to cause systemic side effects.
OncoSec's OMS platform is currently being evaluated for two different types of therapies. NeoPulse utilizes the chemotherapy agent, bleomycin, which has been evaluated in Phase III trials successfully against head and neck cancer. Details of these results are certainly worth investigating, but are beyond the scope of this article. The company's ImmunoPulse platform utilizes electroporation to administer DNA IL-12, a plasmid DNA construct coded with instructions for the cells to produce the IL-12 cytokine. The therapy is injected at the targeted tumor site where it is subsequently electroporated. This electroporation keeps the toxic IL-12 cytokine localized in the tumor area with little left circulating throughout the body. Cells that produce (or express) the IL-12 are recognized as foreign by the immune system and are attacked accordingly.
Like Ziopharm's Ad-RTS IL-12, clinical data indicate a systemic response against the targeted cancer type rather than just a local response at the administration site. However, I believe the likely lysing (cell disintegration/degradation) induced by the electroporation technique provides for much more efficient exposure of the specific cancer cell type's antigens to dendritic and antigen-presenting cells (APCs) than the simple intratumorally-injected IL-12 of old or even perhaps more efficient than Ad-RTS IL-12.
In other words, the more efficient breakdown of the cancer cells via the electroporation (electro-shock) procedure gives more cell fragments (proteins, etc.) for the dendritic cells and APCs to use and create an immune response against those cell types, not just the cells locally producing the IL-12 cytokine. If this is the case, then the systemic immune response against the targeted tissue type may be stronger and more robust.
An example of this type of presentation is seen in an article addressing the immunotherapy approach to targeting glioblastoma (brain cancer). The article notes:
Several antigen sources can be used for active immunotherapy such as intact tumour cells, tumour protein lysates (of particular note for my case), tumour-derived mRNA, peptides eluded from tumour MHC class I molecules, and synthetic peptides. Antigens can be used alone and injected in the presence of different adjuvants or presented on DCs which play a key role in initiating the immune reaction.
Time and clinical data will only tell if the increased cell lysate produced from the electroporation device is a significant variable, or if the majority of the immune system "learning" what the cancer cells look like is due to the local exposure of the dying cells that have been attacked by natural and killer T-cells and IFN gamma production.
The company has two on-going Phase II trials underway and had interim data released in Q4 2012, each with promising results. On October 23rd OncoSec presented Phase II data evaluating the ImmunoPulse platform's treatment for Merkel cell carcinoma (MCC). Of the small 5-patient trial enrolled so far, two patients withdrew after one of the two treatment cycles due to disease progression. The three remaining patients were treated with two cycles of the therapy and had increased levels of IL-12 expression in tumor biopsy sampled three weeks post-treatment relative to pre-treatment sampling.
Of these three, one had a confirmed response (over 70% regression) that had persisted for about 8 months at the time of the data unveiling. The safety profile of the regimen has been impressive so far with it being construed as safe and well-tolerated with grade one pain and grade one injection site reaction with no discernible systemic toxicity.
On November 15th, OncoSec presented interim data from its ImmunoPulse platform's trial evaluating its efficacy and safety in treating patients with the larger indication metastatic melanoma. Interim data in the 15-patient trial noted 13 subjects were evaluable at 39 days, 9 at 90 days and 2 at 180 days. 95% of treated lesions demonstrated response at 39 days (14% stable disease (SD), 42% partial response (PR), 39% complete response (CR), at 90 days results were (50% PR, 45% CR) and at 180 days (33% PR and 77% CR). At 180 days, 2 subjects were evaluable for ORR (per the trial's design, ORR is to be measured at 180 days). Of the 2 evaluable patients, 1 had a confirmed stable disease.
The 2nd patient had a near-complete response of all treated and untreated lesions. Ongoing updates and interim data analyses will be key for this trial. Continued systemic immune response against the melanoma tumors throughout the patients' bodies would be a sign of a trained immune system fighting the cancer on its own. Long-term immune response is also key, ensuring the response is both robust and effective.
OncoSec Medical is a microcap company with a current valuation of only about $19.6 million at market close on Monday, December 24th. It is still dependent on investors' capital to fund its operations, typical of small cap development-phase pharmaceuticals. On December 13th, the company announced a $7.3 million offering to fund the development of its research. Although dilutive to existing shareholders, the ensuing share price drop from the previous day's $0.31 to the opening price on December 13th of $0.23 does allow for a better entry for new investors. Still trading in the low $0.20s, the upside here could be significant if interim Phase II data updates begin giving more indications of the ImmunoPulse's safety profile and efficacy against not only the targeted, but also the distant lesions (tumors). Downside risk is obviously there if the trials fail.
However, the NeoPulse platform's success in using the chemotherapy agent, bleomycin, provides for some diversification with promising Phase III data behind them, and a CE mark to the company's credit as of October 17th. Another catalyst "lying in wait" is any announcement from the company pertaining to licensing or partnering out the NeoPulse platform as hinted at in my October 1st interview with company CEO, Punit Dhillon. Pertaining to the NeoPulse platform, especially for the head and neck cancer indication, Mr. Dhillon stated:
Our focus for the NeoPulse program is to present the data to a number of specifically targeted potential partners for their evaluation as a license opportunity. If we can land a partner for this program, which we see as a near-term commercial opportunity, then we feel that this would be a significant validation of our data and the NeoPulse program.
Merck Serono's Humanized Antibody Delivery of IL-12
Even the $126 billion pharmaceutical giant, Merck (NYSE:MRK), is evaluating IL-12's hope in treating cancer. Although the company's upside potential isn't as great with a successful development of its candidate, the company's common shares do represent a safer bet for those investors desiring a more stable company with virtually no downside due to any failure of its IL-12 evaluation for cancer treatment. The company's candidate, NHS-IL 12, is being evaluated for its potential in treating solid tumors, like the previous two candidates.
Partially validating the concept of systemic response to a certain tumor type as a result of treating one or a few tumors with IL-12, Merck describes the therapy as "an investigational cancer immunotherapy that is designed to target the DNA fragments released from the dead and dying (necrotic) cells found in the context of many solid tumors." NHS-IL 12 is actually a novel immunocytokine formed by linking two molecules of IL-12 to a fully humanized antibody termed NHS76. This antibody is designed to target dead cancer cell portions of tumors because of its high affinity for single- and double-stranded DNA, which are exposed as tumors outgrow their blood supplies and die.
A Phase I trial investigating NS-IL 12 for the treatment of solid tumors is currently underway that is sponsored by the National Cancer Institute (NCI). Preclinical data evaluating the use of the antibody-cytokine pairing was promising in mouse models. Data indicated superior in vivo localization of IL-12 (concentration of IL-12 cytokines) in mouse tumors following subcutaneous NHS-IL 12 injection relative to administration of recombinant IL-12 (rIL-12) or IL-12 fused to a control antibody (BC1).
Most interestingly, however, was the comparison of NS-IL 12 administered in vitro (outside the body in a "test tube setting") relative to in vivo (in the body, in a real-world biologic setting). In mice having MC38/CEA+ colorectal carcinoma, NS-IL 12 "significantly delayed subcutaneous tumor growth" more effectively than those injected with typical IL-12 intratumorally. However, NHS-IL 12 did not inhibit MC38/CEA+ tumor cell growth in vitro. This indicates that the therapy acts indirectly in the mouse models via a learned immune response.
The current NCI-sponsored Phase I trial is targeting patients with metastasized solid tumors that have not responded to standard treatment regimen. The accrual ceiling for the trial is 78 patients with 2 patients per month being enrolled. Of special note on the administration of NS-IL 12 is its injection per its trial description at clinicaltrials.gov. It is described as injected "subcutaneously as a onetime dose in patients with metastatic or locally advanced solid epithelial or mesenchymal tumors." The therapy will simply be injected as a typical vaccine under the patient's skin, not into the tumors (intratumorally). The trial is expected to be completed in July 2014, although I expect to see data out earlier, such as in ASCO's annual meeting in late May/early June of 2014.
Merck's common shares are now trading at $41.42, with a 52-week range of $36.91-$48.00. The company's shares had a recent setback due to failure of its late-stage HPS2-THRIVE trial evaluating TREDAPTIVE's (extended-release niacin and laropiprant) effect on the combination of coronary deaths, non-fatal heart attacks, strokes, or revascularizations compared to statin therapy alone. This setback may make a prime entry position into one of the world's most successful pharmaceutical giants. A safer investment than the other two alternatives, its upside is obviously not as significant if NS-IL 12 is successful. However, the company's $0.42 quarterly dividend does offer additional incentive and is a better investment for certain investor types.
According to the National Cancer Institute, more than 1.55 million people will be diagnosed with a malignant solid tumor in 2012. The need for treatment is obvious, and the discussed IL-12 treatments above may very well represent hope for this large group of patients. Investment potential for each of these candidates is promising. Merck's upside would be limited in the event of success with its Phase I trial, but so would its downside if it suffered a setback. Ziopharm's market capitalization and current share price is in large part due to palifosfamide's potential in treating SCLC.
However, success in its Phase II trial evaluating Ad-RTS IL-12 for melanoma could be a large share price driver in coming months if interim data proves to be promising. OncoSec's ImmunoPulse Phase II trials underway have shown early-stage success for the $19.6 million development phase company. The next interim data evaluations are critical for this company as these trials will have more enrolled patients and should give a better indication of the systemic response seen in the early interim data sets. I believe that it is possible that the destruction of cancer cells at the electroporation probe administration site could provide for additional cell fragments for the dendritic cells and APCs to use and create a systemic immune response against those cell types; in addition to the local ImmunoPulse-induced IL-12 expression by the targeted tumor cells.
Interested investors are advised to closely evaluate each company's upside and downside potential with the upcoming catalysts in mind. Ziopharm and OncoSec are both development-phase entities requiring occasional share offerings to fund their operations, which has been taken into consideration with their smaller market capitalizations.
Merck is an established company with a large pipeline and is generating over $2 billion in income quarterly. With varied IL-12 therapies under development, varied upside potential and downside risk and differing catalysts and futures ahead, interested investors should consider this article to be only the beginning of their research into these promising companies.
Additional disclosure: I may initiate a long position in ZIOP over the next 72 hours.