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Neoantigens Hold Promise in the Development of Novel Cancer Immunotherapies

Killer T Cell: The Cancer Assassin

Introduction to Neoantigens

The immune system is a complex network of organs, tissues, and specialized cells that acts to defend the human body. In healthy individuals, when a microbe invades the body, the immune system recognizes it as “foreign,” destroys it, and remembers it to prevent another infection, should the microbe invade the body in the future.

The cells that provide targeted protection against specific threats are called lymphocytes. These lymphocytes, such as B cells and T cells, circulate in the blood, recognize foreign substances, and destroy or neutralize them.

Invading bacteria and viruses are recognized by the immune system as a threat because they carry foreign or “non-self” proteins, or antigens. These foreign antigens alert the immune system so that it can recognize and clear the invader. Bacteria and viruses are not the only threats recognized by the immune system – when cancer arises, tumor cells develop unique genetic sequences and express abnormal proteins.

These newly formed tumor-associated antigens arise as a consequence of cell mutations and are referred to as neoantigens. Generally, neoantigens appear more “foreign” to the immune system and are therefore more immunogenic than tumor-associated “self” antigens (which may be present on tumor cells as well as some normal cells) but still not quite as immunogenic as foreign viral antigens.

Thus, neoantigens may be used by the immune system to slow or even halt cancer progression. This concept has been known for some time, for instance, in preclinical mouse tumor models, mice lacking intact immune systems were shown to be more susceptible to exposure-induced and spontaneous cancers compared to their immunocompetent counterparts.

Neoantigens in Cancer Immunotherapy

Cancer researchers have long sought to develop therapies that harness the immune system’s ability to recognize and attack malignant cells. The body’s own immune system can mount a targeted defense that may produce less collateral damage than conventional chemotherapy or radiation therapy. Moreover, the immune response has the potential to continuously evolve and adapt to genetically unstable, continuously changing cancer cell populations.

However, only in recent years, with rapid advances in genome sequencing, have neoantigens become feasible targets for cancer immunotherapy. Researchers can now sequence the entire genome of a tumor and compare it to an individual’s normal cells to identify all the mutations that have occurred. This research is leading to increasingly comprehensive maps of cancer genomes. These maps have provided researchers with insights into mutations recurring at high and moderate frequencies across tumors. These maps also show the mutations unique to each patient.

Despite an improved understanding of cancer mutations and the mechanisms by which the body is able to distinguish cancer cells from non-cancer cells, researchers have faced multiple challenges when attempting to develop effective immunotherapies, including:

  • The ability to generate a potent immune response (applying the immune system’s “gas”)
  • The ability to direct T cells the site of the cancer (“steering” the immune response)
  • The ability to promote a sustained immune response capable of clearing the cancer (removing the immune system’s “breaks”)

Recently, however, there have been important breakthroughs in the field. In particular, the introduction of checkpoint inhibitors. Many cancers protect themselves from the immune system by inhibiting proper T cell signal functioning. Checkpoint inhibitors release the “brakes,” allowing the immune system to reactivate a potent anti-cancer T cell response.

Since 2011, several successful checkpoint inhibitors have been approved by the U.S. FDA, including ipilimumab (Yervoy®), pembrolizumab (Keytruda®), and nivolumab (Opdivo®).

The development of checkpoint inhibitors has brought scientific discussion of neoantigens to the forefront. In particular, neoantigens may help explain why certain patients and cancers respond to checkpoint inhibitors while others do not.

There is increasing evidence suggesting that patients with the best outcomes have cancers with significantly more neoantigens that are more easily recognized by the immune system. Likewise, patients with cancers that have limited neoantigens tend to have limited anti-cancer immunity even when the “brakes” are released with checkpoint inhibitors.

Given that many tumor-associated antigens are poorly immunogenic, there is growing interest in exploring vaccination with more potent neoantigens, or foreign viral antigens that are tumor-associated, such as human papillomavirus (“HPV”) antigens, which are currently used to prevent and may eventually be used to treat cervical cancer.  Similarly, vaccination with cytomegalovirus (“CMV”), a foreign virus easily recognized by the immune system and which is present in many tumors, may represent one novel approach.

VBI’s GBM Immunotherapy Approach

Glioblastoma is among the most common and aggressive malignant primary brain tumors in humans. A growing body of literature suggests that CMV is associated with several cancers, including glioblastoma multiforme (“GBM”). Research indicates that CMV nucleic acids and genes are present in more than 90% of GBM tumors.

CMV antigens are inherently immunogenic and, given their high association with GBM, may serve as an ideal neoantigen targets for a GBM immunotherapy. In October, VBI announced that it is leveraging its expertise in CMV to develop a therapeutic vaccine candidate directed against glycoprotein B and pp65, two CMV antigens that are highly immunogenic targets during natural infections. The vaccine candidate utilizes VBI’s eVLP Platform and includes an adjuvant that mobilizes dendritic function and enhances Th1-type immunity.

Preclinical results so far have been promising. Ex vivo studies have demonstrated the GBM vaccine candidate’s ability to stimulate immunity in peripheral blood mononuclear cells (“PBMCs”) harvested from healthy subjects and patients with GBM. The vaccine candidate stimulates strong helper and cytotoxic T cell responses, key biomarkers associated with positive clinical outcomes. In vivo data confirmed the vaccine candidate’s ability to induce desired T cell responses in mice.

Pilot (10L) scale production of VBI’s GBM vaccine candidate is now underway at a GMP-compliant facility. During recent testing, VBI employed electron microscopy to confirm the integrity of its bivalent eVLPs, with positive interim results. Purity measurements are expected to meet regulatory requirements for clinical evaluation of the vaccine candidate. A pre-IND meeting is planned with the U.S. FDA in H1 2016.

To learn more about VBI’s GBM Immunotherapy Program, visit: http://www.vbivaccines.com/gbm/

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