December 1, 2016 (Vol. 36, No. 21)

Vaccines Are An Important Part of Predictive, Personalized, Preventive and Participatory Medicine

Leroy Hood, M.D., Ph.D., president and co-founder of the Institute for Systems Biology, has predicted that a “new medicine” is coming, some aspects of which are already in their early stages. He says the new medicine will be predictive, personalized, preventive, and participatory (P4). “Molecular diagnostics will provide the tools to identify and predict disease. Systems approaches will generate preventive drugs or vaccines, plus the focus on wellness will be a powerful preventive,” according to Dr. Hood.

One of the rapidly growing areas of P4 medicine can be found in therapeutic cancer vaccines, a number of which are already undergoing intense R&D and clinical studies. These biological response modifiers, which can be classed as preventive or treatment vaccines, work by stimulating or restoring the immune system’s ability to fight infections and disease. GEN spoke to representatives of several companies that are focused on therapeutic cancer vaccines to get a status report on this promising area of P4 medicine.

GEN’s panel of experts

GEN: Would you describe your specific approach to therapeutic cancer vaccine R&D?

Dr. Castle: Agenus’ approach to cancer vaccines starts with genomics, bioinformatics, and computational immunology. It involves identification and characterization of tumor neoantigens unique to each patient using next-generation sequencing (NGS) for rapid profiling of the mutational signature of the tumor.

 Advanced bioinformatics algorithms, mass spectrometry, and structural biology modeling analyses are then utilized to determine the antigenic peptide repertoire that arises from these mutations, enabling us to create the so-called vaccine “blueprint.” Our vaccine format is based on heat shock protein (HSP) Hsc70, which in addition to our adjuvant QS-21 Stimulon® enhances immunogenicity.

Dr. Nejadnik: Galena has in-licensed its cancer vaccine assets. Most therapeutic agents are focused on treatment of advanced cancer, but rarely on the prevention of recurrence in an adjuvant setting once a patient is clinically diagnosed as “disease free.” This leaves a significant area of unmet medical need where Galena is targeting within its development programs.

The company is developing its programs as single agents and also is poised to push forward with combination immunotherapy, in more advanced disease, which is the focus of great interest in cancer treatment.

Dr. Swanson: Clinically in glioblastoma, we leverage the power of a patient’s immune system by treatment with autologous dendritic cells, primed with cancer stem cell antigens. Careful selection of target antigens induces a focused cytotoxic T-cell response that can eliminate residual tumor remaining after debulking.

 This approach can educate the immune system to provide long-term surveillance preventing tumor recurrence.

 We have a novel Stem-to-T-cell approach in research designed to drive some of the patients’ hematopoietic stem cells into generating T cells directed against a specific tumor antigen. We are also developing ways to improve dendritic cell immunotherapies.

Dr. Lam: Immunophotonics is developing an in situ autologous cancer vaccine called inCVAX, “in-SEE-vax.” It is a two-step procedure that generates the therapeutic vaccine inside the patient’s body using his/her own tumor.

First a palpable tumor is primed using a thermal gradient to liberate tumor neoantigens. Next, an intratumoral injection of our immunostimulant GC promotes an adaptive immune response. Our initial nonclinical and clinical studies suggest that inCVAX is capable of eliminating primary tumors and metastases. Immunophotonics has initiated a randomized, controlled breast cancer clinical trial for inCVAX and continues to study the treatment in a variety of nonclinical models.

Dr. Ang: Neon Therapeutics is focused on using neoantigen-based targets in its cancer vaccines. Neoantigen targets are inherently tumor-specific, should not be subject to central tolerance, and, as non-native sequences, are thought to be far more immunogenic than tumor-associated antigen targets.

Since neoantigens are generally unique and specific to each tumor and patient, one approach is to create a fully individualized treatment requiring tumor and normal tissue sequencing, mutation calling, epitope selection and design, and ultimately individualized manufacturing to create a bespoke medicine for each patient. Separately, Neon is researching shared neoantigen targets, which could be used for off-the-shelf vaccine products. 

GEN: What are some major hurdles that need to be overcome in developing an effective cancer vaccine?

Dr. Castle: A number of challenges are associated with individualized vaccines: collecting high-quality tumor material, tumor heterogeneity, the speed of obtaining the tumor fingerprint using NGS, identification of targets that are most immunogenic, and the speed of “on-demand” manufacturing. When it comes to off-the-shelf vaccines, determining target prevalence for each indication and ensuring that that target is not expressed in normal healthy tissues are key hurdles. Vaccine format and adjuvant choice are also important considerations.

Lastly, determining which immunomodulatory antibodies pair well with vaccines and optimizing dosing schedules, both in the context of monotherapy and combination therapy, present additional challenges.

Dr. Nejadnik: The immune system consists of complex and interdependent elements. It functions though a combination of immune activation and tolerance pathways in a physiological satiation and even more sophisticated in pathological situation. Vaccination is the ultimate active immunotherapy for preventing recurrence or slowing down the disease progression.

It is difficult to predict the direct cause and effect in immunotherapy and even more in the case of cancer where immune tolerance has settled and the cancer has broken though the immune defenses. There is a growing consensus that combination therapies, including vaccination, may yield the greatest clinical benefit.

Dr. Swanson: Harnessing the extraordinary power of the immune system to battle tumors could revolutionize oncology treatment. To fully benefit from immunotherapies, it is critical to improve efficacy against larger tumor burden while still protecting patient safety. Autologous treatments have the benefit of safety, and improvements are under way to make them more efficacious.

Cancer stem cells are important targets for immunotherapies because they are resistant to traditional chemotherapy, and surviving cells can result in tumor recurrence. Educating and unleashing the immune system against tumors can only be an effective treatment option if the immune response is focused, but controlled, to protect patient safety.

Dr. Lam: Challenges include tumor immunosuppression, expression of quality tumor antigens, and appropriate treatment combination, among other things. Tumor immunosuppression undermines the effects of any vaccine and while checkpoint inhibition re-invigorates T lymphocytes, suppression via myeloid cells like iDCs, MDSCs, etc., remains a persistent problem.

Furthermore, the efficacy of a vaccine is influenced by the quality of tumor antigens and the homogeneity in their expression on tumor cells, which unfortunately varies from patient to patient. Finally, personalizing a patient’s treatment regime can often require the identification of a synergistic combination of therapies.

Dr. Ang: Historically, cancer vaccines have had difficulties demonstrating substantial efficacy. At Neon, we believe this is for three reasons. Firstly, traditional cancer vaccines have focused on tumor-associated antigens, which have poor specificity and are often subject to central tolerance. This is why Neon is focused solely on leveraging neoantigen targets.

Secondly, we now have complementary drugs such as immune checkpoint inhibitors that can modify the local tumor microenvironment, potentially making tumors more amenable to a vaccine approach.

Lastly, Neon believes that comprehensive immune monitoring is vital to generate insights in tumor biology and mechanism of action.

GEN: What cancer vaccines do you currently have in development for which types of cancer? Where are the vaccines in terms of their stage of development?

Dr. Castle: We have three heat shock protein (HSP)-based vaccine platforms. Prophage™, our autologous tumor-derived vaccine, yielded prolonged survival in a Phase II trial for newly diagnosed glioblastoma. AutoSynVax™, our personalized platform, leverages NGS tumor profiling and just-in-time synthesis of neoantigens algorithmically predicted to be most immunogenic. AutoSynVax™ will enter the clinic within the next six months. PhosphoSynVax™ is our off-the-shelf vaccine platform that targets shared immunogenic tumor-specific phosphopeptides. This platform is in preclinical development.

Dr. Nejadnik: NeuVax™ (nelipepimut-S) is in development to prevent cancer recurrence. Two Phase II trials are ongoing in combination with trastuzumab in HER2 1+/2+ breast cancer. One Phase II trial is planned in early-stage breast cancer known as ductal carcinoma in situ (DCIS) and a Phase II trial is planned in gastric cancer. GALE-301/GALE-302 are in development in Phase I and Phase II trials to prevent recurrence in ovarian, endometrial, and breast cancers.

Dr. Swanson: ImmunoCellular Therapeutics is developing dendritic cell (DC)-based therapies for treatment of brain cancer and other tumors. Lead product candidate ICT-107, in a Phase III registrational trial, targets multiple tumor-associated antigens for newly diagnosed glioblastoma. ICT-121, which targets the CD133 stem cell antigen in recurrent glioblastoma, is in a Phase I trial. ICT-140, which targets stem cell-associated antigens in ovarian cancer, is awaiting resources to advance into Phase II. The Stem-to-T-Cell research-stage program engineers the patient’s hematopoietic stem cells to generate antigen-specific cancer-killing T cells.

Dr. Lam: Our lead treatment, inCVAX, is currently undergoing preclinical development for a variety of palpable solid cancers in support of U.S./EU IND activities. Additionally, we have initiated a breast cancer trial in South America as a follow-up to an earlier investigator-initiated first-in-human trial.

Dr. Ang Neon: Therapeutics recently initiated its own company-sponsored Phase Ib trial studying NEO-PV-01 with nivolumab in three active-disease indications: non-small cell lung cancer, bladder cancer, and melanoma. We are leveraging 8+ years of R&D from our founders, including clinical development work conducted at the Dana-Farber Cancer Institute (DFCI)under the guidance of Neon founder Catherine Wu. DFCI has been already studying personalized neoantigen vaccines in two Phase I trials in the adjuvant setting. 

Cancer Immunotherapy: A Technology Provider’s Perspective

The cancer immunotherapy field is rapidly evolving, with a number of different therapeutic strategies currently under investigation. These therapies can be based on recombinant proteins such as monoclonal antibodies, or can be developed as an active immunotherapy (also called a cancer vaccine) using vectored viruses or even engineered cells.

Academia and smaller biotech companies are driving many of these newly developing immunotherapies, but larger biopharmaceutical companies are investing significantly in the area as well. All of these producers can benefit from process development and technology expertise in the biomanufacturing space, as well as single-use solutions, to keep manufacturing flexible and manage production costs for these types of cancer therapies.

Plan Manufacturing Early

GE Healthcare provides tools for the monoclonal antibody production technology space and is active in other immunotherapy applications, such as virus production and cell expansion. As with all new therapies, biotech/biopharma companies must consider manufacturing logistics while a therapy is still in early development.

“Many smaller innovator companies and academia lack the resources needed to implement large-scale manufacturing of these types of advanced immunotherapies,” says Mats Lundgren, Ph.D., customer applications director, GE Healthcare Life Sciences.

“So to ensure product safety and efficacy, and to keep production costs competitive, they often seek advice and guidance from experienced vendor partners like GE to help develop their process and offer the right technology and consumables. Oftentimes, those solutions demand special production and purification technologies due to the complexity of these drugs.”

Immunotherapies can be very diverse and with high failure rates in the clinical development, so flexible manufacturing solutions for their production are a necessity, according to Dr. Lundgren. In the past, pharma companies invested in fixed, stainless steel manufacturing facilities long before they had proof of concept of their new treatments. However, the rise of single-use production technologies had enabled more flexible production, which in turn has lowered and offset the upfront investment for therapy producers.

“Single-use technologies are in most cases more cost-efficient and suitable for these types of drugs,” points out Dr. Lundgren. “Ultimately, GE Healthcare is helping to offer the start-to-finish manufacturing solution as well as the application support and expertise to help immunotherapy producers bring their therapies to market.”

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