Immunotherapy, the science of modifying, albeit enhancing or suppressing, an immune response to fight a disease or condition, is one of the hottest topics today in biotechnology. Cancer immunotherapy, or immuno-oncology as it’s often called, is particularly popular for its great potential for specific destruction of tumors without damaging healthy tissue, while also reducing the chance of patient relapse. A rudimentary scenario to explain one way cancer cells slip past the immune system is that of the PD-L1 (Programmed Death-Ligand 1) protein, a protein suspected as an immune suppressor in cancer and other diseases. The immune system contains cells that fight disease known as T-cells. However, if a cancer cell has a PD-L1 molecule on its surface, a process is initiated that keeps the T-cell from recognizing it as an antigen, thus failing to attack it and supporting cell proliferation.
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Merck’s (NYSE: MRK) Keytruda and Bristol-Meyers Squibb’s (NYSE: BMY) Opdivo are two well-known drugs that act upon the PD-L1 pathway to allow the immune system to recognize and fight cancer cells that are approved for the treatment of non-small cell lung cancer. Keytruda was first approved as a therapy for metastatic melanoma in 2014 and is being studied in other cancers, such as bladder cancer, with optimistic results. Opdivo (as well as Opdivo plus Bristol-Meyer’s Yervoy) is also approved for metastatic melanoma, demonstrating the potential of immunotherapies to address more than one type of cancer and the efficacy possible through combination therapies.
While Merck and Bristol-Meyers are giants in the drug space, smaller companies, which are often considered the lifeblood of biotech innovation, are deserved of recognition for their clinical research to corral the power of the immune system in a bid to bring new products to market.
Lion Biotechnologies (NASDAQ: LBIO) is focused on developing novel cancer immunotherapies based on tumor infiltrating lymphocytes (TILs), an approach called “adoptive T-cell” therapy. Dr. Steven Rosenberg, chief of surgery at the National Cancer Institute, developed this approach, which involves removing and isolating TILs from a patient’s tumor, expanding them in vitro and then infusing these highly activated potent TILS back into the patient. Lion has a Cooperative Research and Development Agreement with Dr. Rosenberg for exclusive rights to the new adoptive cell therapy technologies for treating metastatic melanoma. Lion’s most advanced product candidate, LN-144, has completed a Phase 2 trial in partnership with the NCI evaluating a TIL infusion in heavily pretreated patients with metastatic melanoma.
In the randomized, Phase 2 trial, a total of 101 advanced metastatic melanoma patients were equally divided between two treatment groups. Both groups were treated according to standard TIL protocol using chemoablation, with the second group also receiving total body irradiation. Treatment with autologous TIL followed by interleukin 2 resulted in an overall response rate (ORR) of 54% in both arms combined, which is an improvement over existing therapies. Twenty-four patients had complete responses; of these patients, 23 showed durability of this response at 30 to 47 months following treatment. Median follow-up time was approximately 35 months. There were no significant differences in clinical outcomes between patients who received total body irradiation and those who did not, meaning that durable responses were demonstrated regardless of prior treatment.
Elsewhere in the pipeline, Lion in September opened enrollment in a Phase 2 trial on LN-144 for refractory metastatic melanoma patients. In June, Lion received an FDA orphan drug designation for the treatment of stage 2b to stage 4 malignant melanoma. Further, in October Lion obtained an exclusive worldwide license from the National Institutes of Health to develop and commercialize TIL therapy in four additional tumor indications, comprised of bladder, lung, breast and HPV-associated cancers, including cervical and head and neck.
OncBioMune Pharmaceuticals (OTCQB: OBMP) is working on an array of innovative cancer therapies, including targeted transferrin transport technologies, antisense oligonucleotides and cancer vaccines. The company owns proprietary rights to a therapeutic cancer vaccine that decades of laboratory and years of early-stage clinical research show to be effective with virtually no toxicity. OncBioMune is most advanced in clinical trials using its prostate cancer vaccine, called ProscaVax, which utilizes Prostate Specific Antigens (PSAs) to immunize patients. PSA, a protein produced by the prostate gland, is commonly elevated in prostate cancer patients and closely monitored as a measure of disease progression in men diagnosed with prostate cancer. The company also leans on interlukin-2, as ProscaVax contains a combination of PSA, IL-2 and GM-CSF (granulocyte-macrophage colony-stimulating factor). Colony-stimulating factors help bone marrow in producing blood cells and to support antigen presenting cells, and thereby the immune system.
The vaccine was built upon a similar technique used to treat breast cancer, with low toxicity of the platform demonstrated in hundreds of patients. The U.S. Department of Defense has supported development of ProscaVax with $5.2 million in funding through the Navy Cancer Vaccine Program. Getting support from the DoD likely made the decision to focus on prostate cancer and easy one, given that its the third most common cancer in the U.S., an estimated 2.8 million American men are living with the disease and about $7.1 billion was spent on prostate cancer drugs last year.
Of particular interest is the nature of the ProscaVax therapy to target patients across the prostate cancer spectrum, including early stage disease, a period where watchful waiting/active surveillance is the only real option without potential for major morbidity (i.e. surgery, radiation, brachytherapy). This also broadens the potential patient population into the hundreds of thousands, rather than smaller subsets that are targeted by most drugs in development. In advanced stages of prostate cancer, which is where most drug development is focused, toxicity is overlooked to a certain degree as extended survival time takes precedent. The low toxicity demonstrated by ProscaVax is a unique opportunity to treat disease at an early stage, while noting that it could potentially be used with other therapies, such as PD-L1 drugs, to further improve outcomes at varying stages.
In the initial trial, 12 previously untreated prostate cancer patients received an initial course of six vaccinations of ProscaVax. Neither before nor during the trial, did the prostate cancer patients receive other concurrent therapy (surgery, hormone, radiation, radioactive seeds, chemotherapy). The patients then additionally received three further vaccinations alternated with low dose IL-2 for the 6 months following the initial vaccinations. No dose-limited adverse events were observed. Serum PSA concentrations were determined before initiating vaccination and 3-4 weeks after the sixth vaccination. Two-thirds of the prostate cancer patients’ PSAs decreased after vaccination.
ProscaVax is now nearing the end of its Phase 1A clinical trial, hosted at the University of California San Diego Medical Center and Veteran’s Hospital in La Jolla, California, in treating recurrent prostate cancer patients with rising PSAs that have not been treated by, or are not responsive to, hormonal therapy. Data from the trial was presented in October at the CRI-CIMT-EATI-AACR: Inaugural International Cancer Immunotherapy Conference in New York City. OncBioMune anticipates completion of this trial next month and is now preparing for a 120-patient Phase 2 trial at the Dana-Farber Cancer Institute. The company has already raised capital for this larger trial, including a $10 million share purchase agreement with Lincoln Park Capital Fund. It’s fair to say that it is unusual to see such a small company being well funded and conducting a clinical trial with a novel cancer vaccine at such an esteemed cancer center as Harvard’s Dana-Farber.
Advaxis (NASDAQ: ADXS) is a clinical-stage biotechnology company that has taken a different immunotherapeutic approach to try and destroy cancer cells. With its Listeria monocytogenes (Lm)-LLO immuno-oncology technology licensed from the University of Pennsylvania. Advaxis uses live attenuated bioengineered gram-positive bacteria to stimulate the immune system to selectively target tumor cells for elimination.
The company calls this a Trojan Horse approach because its genetically engineered bacteria trick the immune system into thinking cancer cells (which, as aforementioned, can evade the immune system) are bacterial infections. To wit, the antigen-presenting cells are recognized as foreign, generating an immune response. Advaxis heralds that its cancer immunotherapy is the only shown to actively suppress the key components in the tumor microenvironment – regulatory T cells (tregs) and myeloid-derived suppressor cells (MDSCs) – that protect the tumor from immunologic attack, although researchers, such as those at MD Anderson, are working on peptides that specifically target and destroy MDSCs as well.
Advaxis has several clinical trials ongoing, with most evaluating Advaxis’s lead Lm technology axalimogene filolisbac, a candidate for treating human papillomavirus-associated cancers, including cervical cancer, head and neck cancer anal cancer. The FDA has granted Advaxis orphan drug designation for each of these three indications. A 110-patient Phase 2 study completed in India evaluated axalimogene filolisbac +/– cisplatin in patients with recurrent or refractory cervical cancer. The trial provided data supporting continuing development of the Lm technology, including apparent prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy. Advaxis has submitted a Special Protocol Assessment request to the FDA for a Phase 3 study evaluating the safety and efficacy of axalimogene filolisbac in high-risk, locally advanced cervical cancer.
Aside from axalimogene filolisbac, Advaxis is in the clinic with a Phase1/2 trial in partnership with Merck assessing ADXS31-142 in combination with Keytruda in patients with previously treated metastatic castration-resistant prostate cancer. Also, late in September the first patient was treated in a Phase 1b dose-escalation clinical study of ADXS-HER2 for the treatment of patients with metastatic HER2 expressing solid tumors. ADXS-HER2 has received orphan drug designation by the FDA for the treatment of osteosarcoma.
Cancer researchers have been nose down for decades looking for a way to efficiently and safely harness the power of the body’s immune system. Substantial progress has been made, especially in understanding the function and dysfunction of the immune system that allows tumor cells to evade termination. Because of this progress, immuno-oncology is the elephant in the room providing hope that patient prognoses can be improved and, in the case of early treatment and vaccination by OncBioMune, may have a much better outlook from the outset.