Advaxis Immunotherapies, led by President and CEO Daniel O’Connor, is developing a promising and versatile approach to immuno-oncology with its Listeria monocytogenes (Lm) antigen delivery system. Lm Technology shows the immune system how to identify and target tumors, weakens tumor defense mechanisms, and triggers the immune system to send in its powerful, killer T cells. With phase 3 trials underway in cervical cancer and multiple phase 2 trials in anal, head and neck, prostate and HER2-positive cancers, the Princeton, N.J.-based company has demonstrated significant potential for its antigen delivery system across many cancer types in the clinic. This year, Advaxis, in collaboration with Amgen, is entering the clinic with ADXS-NEO, a neoantigen-based approach that may usher in a new era in precision immunotherapies. 

While the potential of this technology was apparent when Advaxis licensed it from the University of Pennsylvania more than 10 years ago, very promising clinical data has emerged in recent years under O’Connor’s  leadership. He has led the transformation of Advaxis into a leading cancer immunotherapy company with major biopharmaceutical manufacturing partners, such as  Amgen, Merck, and MedImmune.

Before taking the helm of Advaxis, O’Connor held executive leadership positions at ImClone Systems and PharmaNet, now known as inVentiv Health. At ImClone, O’Connor was senior vice president, general counsel, and corporate secretary when the company launched ERBITUX®, and led extensive licensing negotiations in advance of ImClone’s sale to Eli Lilly in 2008. O’Connor also served as a captain in the U.S. Marines, and was an assistant prosecutor in the Somerset County (NJ) Prosecutor’s Office.

As part of a new series on industry innovations, WuXi AppTec Communications asked O’Connor to share his thoughts about new advances in immunotherapy, industry challenges, and trends in innovation.

WuXi: What are we trying to accomplish with immunotherapy?

Daniel O’Connor: The immune system is capable of patrolling your entire body, interrogating and examining every cell and then attacking the cells it deems foreign and harmful. Cancer, however, has the unique ability to evade the immune system and thrive and grow under cover. What we’re trying to accomplish in immuno-oncology, and specifically with our technologies at Advaxis, is to bridge this gap and alert the immune system to the presence of cancer and weaken the cancer’s own evasion and defense mechanisms, and pave the way for killer T cells to attack.

We’re driven to achieve this accomplishment because the current standards of care for many cancers – which are built around toxic chemotherapies, destructive radiation therapy and/or invasive surgeries, or some combination of the three – do not work for everyone, especially those with late-stage cancers.

We have achieved accomplishments of which we are very proud. We have seen significant improvements in disease free progression, unprecedented survival rates (in advanced cervical cancer), including three complete responses and no long-term toxicities, and we’re excited about what lies ahead.

WuXi: How does your approach compare to other immunotherapies?

Daniel O’Connor: What makes the Lm Technology so unique is its versatility. We have found that it has the potential to be paired with a wide variety of antigens. When it comes to ADXS-NEO, our preclinical personalized cancer immunotherapy, the technology has the ability to target potentially hundreds of neoantigens at a time, potentially eliminating the need for a predictive algorithm and ensuring that we are targeting all of the antigens may be causing the patient’s cancer.

The promise of targeting neoepitopes begins with improving the response of T cells. But because of the body’s central tolerance and deletion of self-reactive T-cell clones, naturally occurring T cells have low-affinity properties, meaning they are weak when it comes to binding to and killing off cancer cells. Some immunotherapy technologies that artificially create high-affinity T cells can be toxic.

With our approach, tumor-specific acquired mutations generate peptides that are changed from “normal” that serve as new antigenic targets (neoantigens or neoepitopes) that are not subject to central tolerance. Therefore, they are not toxic to normal sequence peptides in non-cancerous cells. Neoepitopesare the most ideal targets for T cell-based cancer immunotherapy wherever there are no viral or pathogen-associated targets that cause the malignancy.

To date, the best clinical responses have been seen in treatment with PD-1 (PD-L1) and CTLA4 checkpoint inhibitors and from TIL (Tumor Infiltrating Lymphocyte) cellular immunotherapy.

Data shows that patients who have good clinical responses to PD-1 and CTLA4 treatment all were found to have a low level of T cells targeting neoantigens that were pre-existing before treatment. The expansion of these neoepitope-specific T cells under checkpoint inhibition allows the patient to generate enough of these cells to cause the tumors to shrink.

TIL clones with the most anti-tumor power translates to complete responses. TILS always target a tumor neoantigen or neoepitope resulting from a mutation and never target a natural sequence epitope.

That’s why we believe our immunotherapies – which generate new T cell responses against neoepitopes – are uniquely positioned to work without excess toxicity from artificial technology.

WuXi: What have you learned about immunotherapy from your research?

Daniel O’Connor: Our preclinical and clinical research has shown our Lm Technology to be tremendously versatile, scalable and compatible. We’ve always known that cancer is caused by mutations, and we know immunotherapies are most effective when T cells are directed against the very mutations that cause cells to become cancerous in the first place. At Advaxis, our research has shown us the power of the Lm vector to direct the full attention of the immune system against these mutations just like if it was responding to a bacterial infection.

We’ve also learned a great deal about immune tolerance and the multiple mechanisms that protects cancer cells, but we do not know them all. Two elements that protect cancer in the tumor microenvironment that we do know well are regulatory T cells and MDSCs that have the ability to shut down a T-cell response. Lm Technology has shown to reduce the ability of regulatory T cells and MDSCs to ward off a T-cell response in a mechanism that is distinct from and synergistic with checkpoint inhibition.

We continue to get excited about how the bioengineered and attenuated Listeria monocytogenes vector both brings a response based on whichever antigen we are presenting, as well as the way it simultaneously reduces these tumor protection mechanisms.

WuXi: What are some future trends in immunotherapy?

Daniel O’Connor: We see two trends already taking shape in immunotherapy. First, given the complexities and multiple layers of the immune system and tumor microenvironment, we know the potential of combination therapies holds significant promise. Second, and even more exciting, we see a move away from the one-size-fits-all approach to treating disease as we start to focus more and more on bringing patients personalized therapies tailored to their specific cancers.

Let’s take the second part of that equation first. Advances in gene sequencing and new efficiencies in manufacturing have empowered several biotech companies, including us, to explore a neoantigen-based approach to immunotherapy. We can now quickly identify the mutations that are specific to an individual patient’s tumor, enabling us to bioengineer a truly customized and targeted therapeutic. While we are incredibly excited about our collaboration with Amgen on our neoantigen approach in ADXS-NEO, which we believe will bring a truly personalized approach to immuno-oncology, many others are working towards the same goal. As a matter of fact, internet billionaire Sean Parker and his Parker Institute for Cancer Immunotherapy joined forces with the Cancer Research Institute to form a joint effort between industry and academia with the TESLA Consortium.

Immunotherapy will become the backbone for a multi-modality approach to treat advanced cancers. With the superior ability of immunotherapies to eliminate residual cancers following frontline treatment modalities of chemotherapy and radiation, it will be key in preventing disease progression and recurrence. With checkpoint inhibitors and therapeutic vaccines, such as axalimogene filolisbac which is being tested in phase 3 studies for advanced cervical cancer, there are significant changes coming to maintenance therapy and the adjuvant therapy setting, and these immunotherapies just as easily have the potential to be added to the standard of care alongside frontline treatments, too.  There’s certainly a paradigm shift coming.

WuXi: What kinds of collaborations over the next several years are essential to your business strategy?

Daniel O’Connor: Advaxis’ Lm-based antigen delivery system has demonstrated the potential to induce an enhanced innate immune stimulation and generate specific T cells while reducing immune tolerance in the tumor microenvironment with a number of potential antigens. We know from pre-clinical studies and multiple clinical trials that our immunotherapies are well-equipped to demonstrate a synergistic anti-tumor response with checkpoint inhibitors (e.g., PD-1 and PD-L1 antibodies) and costimulatory molecules (e.g., OX40 and GITR agonists).

We are opportunistically pursuing collaborations to combine our Lm technology with agents that enhance the anti-tumor activity of our constructs, maximize immune response and guard against immunologic tolerance. Advaxis’ technology can manage many aspects of this approach to target the tumor and the tumor microenvironment, and we know our product candidates work well with checkpoint inhibitors and costimulatory agents to enhance antigen presentation.

In the last six-to-nine months, we announced two such collaborations, one with biotech giant Amgen, and a second with SELLAS Life Sciences.

With Amgen, we are developing ADXS-NEO in a global collaboration to combine our proprietary bacterial vector system with coding for neoepitopes engineered from a patient’s very own DNA and the DNA from that patient’s tumor. Remarkably, ADXS-NEO works by presenting a large payload of neoepitopes or neoantigens directly into dendritic cells and stimulating a T-cell response against cancerous cells, triggering a cell-to-cell battle of T cells against tumors without a response of neutralizing antibodies and a reduction in that tumor’s defense mechanisms.

We also licensed our technology to SELLAS to develop a novel cancer immunotherapy with WT1 antigens that has the potential to precisely direct an immune response, yielding improved clinical activity against many cancer types that express WT1. WT1 is one of the most widely expressed cancer antigens and was named a top target for cancer immunotherapy by the National Cancer Institute.  In addition, we have seen data suggesting how our lead product candidate, axalimogene filolisbac, may work well with checkpoint inhibitors and co-stimulatory molecules.

Advaxis has embraced strategic global collaborations with other major biopharmaceutical companies for the development and commercialization of our proprietary cancer immunotherapies.

WuXi: How should the biopharma industry respond to concerns over drug pricing?

Daniel O’Connor: We are sensitive to the financial burden our cancer patients and families endure and believe our industry needs to take a hard look at where efficiencies can be achieved that will balance the need for industry to recoup product development expenses while also funding the development and advancement of new product candidates to market.

The biopharma industry has the opportunity to become a leader on drug pricing by ensuring access to therapies regardless of financial means. This is a priority area of focus for Advaxis as women and men suffering from rare and late-stage cancers should have access to therapies that can improve and extend their lives when those therapies become available in the U.S. market. Co-pay assistance and other patient support programs are important in helping patients manage cost and being able to continue offering patient support programs will be important to addressing drug pricing concerns.

WuXi: How do you think the 21st Century Cures Act will impact your company?

Daniel O’Connor: The Cures Act is important for Advaxis in a number of ways. First, the Cures Act expands FDA’s recognition of patient experience data in the drug development and approval process. For therapies under development in advanced- and late-stage diseases like Advaxis is studying, the patient experience is so critical to FDA’s understanding of the benefit and risk profiles of investigational products.

The Cures Act also requires FDA to formalize a process for qualification of drug development tools like biomarkers and surrogate endpoints and provides that such tools can be used to support licensure of a product. In the immunotherapy area in particular, there is a need for FDA’s recognition of new tools and endpoints that provide clinically meaningful data in the drug development process, particularly for the advanced cancers we study.  Immunotherapies are on the front lines of working to qualify new endpoints, biomarkers, and surrogate or intermediate endpoints and we expect utilization of FDA’s formal qualification process will become an important drug development strategy for our company and the future products we develop.

WuXi: What other R&D projects are you working on?

Daniel O’Connor: As we move ADXS-NEO into the clinic this year, we have a few more intriguing preclinical programs which we have publicly disclosed, and several additional projects for which we are generating preclinical workups.

First, we entered into a collaboration earlier this year with SELLAS Life Sciences to evaluate Lm constructs developed with WT1. WT1 is widely expressed in several cancers, and SELLAS’ antigen galinpepimut-S has demonstrated positive data in acute myeloid leukemia, malignant pleural mesothelioma and multiple myeloma. It has been shown to induce strong immune responses (CD4+/CD8+) against the WT1 antigen and to access a broad range of HLA types. Coupled with our technology’s demonstrated potential to induce an enhanced innate immune stimulation and generate specific T cells while reducing immune tolerance in the tumor microenvironment, this novel agent could be a very compelling WT1-targeted cancer immunotherapy.

We also are leveraging our technology to target hotspots or the public mutations commonly observed in multiple patient tumors and in multiple tumor types. Through this program, we will be able to develop a library of “off-the-shelf” agents that can be given to patients who test positive for the biomarkers in that specific mutation.

And we’re exploring the potential of dtLLO as an adjuvant molecule for vaccines for infectious diseases.Our detoxified Listeriolysin O, or dtLLO, a nonhemolytic LLO developed by modifying the Listeria monocytogenes bacteria, has shown the potential to stimulate a robust immune response required for prophylactic infectious disease vaccines. Earlier this year, data were published from preclinical studies using dtLLO adjuvant in vaccine preparations targeting Dengue virus serotype 4 E protein in the journal Clinical and Experimental Immunology.

As you can tell, I am incredibly excited about the potential of our proprietary antigen delivery system, as we firmly believe it has tremendous versatility. We believe that we can use our Lm Technology with any number of antigens.