ADVAXIS Lm TECHNOLOGY
A Proprietary Antigen Delivery Platform that Activates the Immune System, Naturally
Lm Technology represents an advancement in the field of immunotherapy, as its comprehensive immune stimulation and priming redirects a “pathogen-like” response against cancers. The Lm Technology vector, the basis of each of our products, is designed to stimulate multiple immunotherapy mechanisms. When compared to traditional cancer treatments such as chemotherapies, Lm Technology product candidates are generally well-tolerated, with mild to moderate, transient adverse events. Importantly, Advaxis’ product candidates have the potential for combination with conventional and novel therapies, including other immunotherapy products that modulate the immune response, such as checkpoint inhibitors, co-stimulatory agents, radiation therapy, and other active cancer therapies.
THE ADVAXIS DIFFERENCE
Through a license from the University of Pennsylvania, Advaxis has exclusive access to a proprietary formulation of attenuated Lm which further enhances the nearly ideal natural system of wild listeria.
Advaxis’s Listeria-based immunotherapies are optimized for antigen delivery through a process of insertion of multiple copies of the proprietary tLLO-fusion protein into each extrachromosomal protein expression and secretion plasmids that make and secrete the target protein right inside the patients antigen presenting cells which initiates and/or boosts their immune response.
The tLLO-fusion protein approach was developed at the University of Pennsylvania as an improvement over insertion of a single copy of the target gene, as an ACT-A (or other Lm peptide) fusion, within the bacterial genome for four key reasons:
1. Multiple copies of DNA in the plasmid may result in larger amounts of tLLO-Fusion Protein being expressed simultaneously, which can can improve antigen presentation, immunologic priming and increases the number of T cells generated for a particular treatment.
2. tLLO expressed on plasmids has been shown to reduce numbers and immune suppressive function of Tregs and MDSCs in the tumor microenvironment. Recently presented data demonstrates that Tregs are being destroyed as soon as 5 days after the first treatment in animal models.
3. The extrachromosal DNA plasmids themselves also contain CPG sequence patterns that trigger TLR-9, which confers additional innate immune stimulation beyond a listeria without the plasmids.
4. The multiple copies of bacterial DNA plasmids (up to 80-100 per bacteria) confers additional stimulation of the STING receptor within APC’s which has been associated with enhancing anti-cancer immunity in patients.
Lm Technology and the Immunotherapy Landscape
The challenge of cancer immunotherapy has been to find the best overall balance between efficacy and side effects when mobilizing the body’s immune system to fight against cancer. Looking back on the last two decades, there have been promising technology advancements to harness and activate killer T cells against cancers and every day more is learned about the interplay between immunity and cancer that can lead to improved treatments. So how does Lm Technology fit into today’s immunotherapy landscape?
The development of immune checkpoint inhibitors was a huge step forward, and brought with it impressive clinical activity in many different types of cancers, including melanoma and lung cancer. However, a literature review published in Pharmacy and Therapeutics in 2016 noted that checkpoint inhibitor monotherapy response rates are only in the 15-20% range, and only rise to around 50% higher in selected groups of patients with melanoma or lung cancer. Therefore, for most cancer patients, there is room for improvement. Checkpoint inhibitors can expand existing cancer fighting cells that may already be present in low numbers and support their activity against cancer cells, but if the right cancer-fighting cells are not present, checkpoint inhibitors may not provide clinical benefit. Similarly, there are many mechanisms of immune tolerance that are distinct from the checkpoints, and they may also be blocking the immune system from fighting cancer. Based on both pre-clinical and early clinical data, Advaxis believes that checkpoint inhibitors, when combined with treatments such as Lm Technology, can have an amplified anti-tumor effect. Lm technology incorporates several complimentary elements that include innate immune stimulation, potent generation of cancer-targeted cells, ability to boost immunity through multiple treatments, supporting lymphocyte infiltration into tumors, reduction of non-checkpoint mediated immune tolerance within the tumor microenvironment, and promotion of antigen spreading which may amplify the effects of treatment. These results provide rationale for further testing of Lm Technology agents in combination with checkpoint inhibitors.
Traditional cancer vaccines were another development within immunotherapy and have a history beginning over 30 years ago. Unfortunately, these vaccines have largely been unsuccessful for a variety of potential reasons. These include poor selection of targets, imbalanced antigen presentation by inclusion of certain immune enhancing agents (adjuvants), failure to consider the blocking actions of immune tolerance, and choice of vaccine vectors. In some cases, patients may develop neutralizing antibodies, preventing further treatments. In contrast to traditional cancer vaccines, Lm Technology takes advantage of a natural pathway in the immune system that evolved to protect us against Listeria infections, that also happens to generate the same type of immunity that is required when fighting cancer. The live but weakened (attenuated) bacteria stimulate a balanced concert of innate immune triggers and present the tumor antigen target precisely where it needs to be to generate potent cancer fighting cells from within the immune system itself. The multitude of accompanying signals serves to broadly mobilize most of the immune system in support of fighting what seems to be a Listeria infection, and is then “re-directed” against cancer cell targets. Additionally, the unique intracellular lifecycle of Listeria avoids the creation of neutralizing antibodies, thereby allowing for repeat administration as a chronic therapy with a sustained enhancing of tumor antigen-specific T cell immunity.
More recently, a new category of immunotherapies called Adoptive Cell Transfer (“CAR-Ts”, “TCRs”, “TILs”) has provided further evidence of the benefits of providing an enhanced T cell presence to fight cancer. As published in the Journal of the American Medical Association in November 2017, CAR-T has achieved dramatic results in liquid tumors, and can provoke clinical responses when other treatments stop working. These cells are artificially engineered outside the body and early versions have suffered from unanticipated side effects. The therapies are also limited in activity against a specific target, and have a limited persistence within the patient. To date, CAR-Ts activity has been limited to liquid tumors and have shown meaningful toxicity concerns. Moreover, CAR-Ts are complex therapeutic products that are primarily manufactured and released for each patient, leading to expensive manufacturing and limited treatments. While Lm Technology has not yet been evaluated in combination with CAR-T cells, it is hypothesized that combination treatment may improve the limited scope of CAR-T cell targets through antigen spreading and potentially facilitate better activity in solid tumor microenvironments.
There are still significant unmet needs in the immunotherapy landscape that Advaxis feels that Lm Technology can address and complement. Specifically, Lm Technology has the potential to optimize and expand checkpoint inhibitor activity in combination. It also avoids many of the limitations of previous cancer vaccine attempts by tapping into the pathway reserved for defense against Listeria infection while incorporating the best cancer-targets science can identify, including neoantigens that result from mutations in the cancer. Lm Technology products have a generally well-tolerated safety profile, do not generate neutralizing antibodies lending themselves to retreatments, and most of the products are immediately available for treatment without the complication and expense of modifying a patient’s own cells in a laboratory.
ADVAXIS™ INTELLECTUAL PROPERTY
We protect our proprietary Lm Technology™ with an extensive portfolio of issued and pending patents in the U.S. and worldwide. Since 2002, we have maintained, through various agreements, an exclusive worldwide license and a right to grant sub-licenses of our Lm Technology™ from the University of Pennsylvania. In addition, we have 160 Advaxis-originated patents and growing, across multiple categories.