By: Dr. Stephen Pelsue

Overview

Neoplasia, or cancer, comes from the Greek meaning “new growth.”  Malignant neoplasms are unrestrained and spread into the surrounding tissue which may lead to physiological impairment.  The “new growth” is a result of genetic changes that limit the effectiveness of normal cell cycle checkpoints and growth parameters.  In many cases, the altered gene expression of the preneoplastic or neoplastic cell can be detected by the immune system through immune surveillance mechanisms which will then target the defective cells and remove them and prevent any harm to the host.  However, continual mutation and adaption of the cancer cells results in developing the ability to evade the immune system and escape detection.  One of the specific mechanisms by which tumors evade detection and removal by the immune system is to develop an immunosuppressive microenvironment that prevents an immunological attack. Recent advances in understanding the immunological checkpoints that are manipulated by cancers have led to new and effective immunotherapies for the treatment of several cancers.

 

Figure 1: CTLA4/PD1 Immune Suppression

Figure 1: CTLA4/PD1 Immune Suppression

Immunological Checkpoints

The immune system has several checkpoints to prevent the development of autoimmune responses as well as to minimize tissue damage during an inflammatory response. Immune responses are modulated by coinhibitory pathways, which control the intensity and duration of a local immune response. These pathways are regulated through ligand-receptor interactions between antigen presenting cells or tissues and T cells (See Figure 1), that when activated will dampen the T cell response. CTLA4/B7, and PD1/PDL1 are probably the best characterized coinhibitory pathways that modify T cell receptor (TCR) signaling. Blocking T cell activation, through coinhibitory pathway activation prevents autoreactive responses and dampens an ongoing inflammatory response, which in both cases would prevent harm to the host.

While the coinhibitory pathways are in place to regulate inappropriate or overactive immunological responses, tumor cells take advantage of these pathways to generate an immunosuppressive environment and evade immune detection and elimination.  Genetic changes in cancer cells not only increase growth advantages, but also alter the expression of coinhibitory ligands resulting in decreased T cell responses towards cancer cells.  The increase in PD-L1 or B7 ligands by cancer cells suppresses the activity of tumor infiltrating lymphocytes (TILS) cells, through the activation of suppressive signaling induced by CTLA4 and or PD1.

 

Cancer Immunotherapies

There are several cancer immunotherapy strategies that are either in use or being developed today.  The most common strategy, at present, is the use of a monoclonal antibody that specifically targets the cancer cells.  Many cancers alter cell surface expression patterns, which allow the cancer to be uniquely identified, or at least target a subset of cells.  The monoclonal antibody therapies have a few mechanisms: cell signaling activation or disruption that leads to cell death, activation of the antibody-dependent cell-mediated cytotoxicity (ADCC), or antibody drug conjugate targeting of the cancer cells.  It turns out that multiple mechanisms are typically involved in effectively targeting and killing the cancer cells.  Specific recognition of the cancer cell may disrupt cell signaling, but also lead to activating ADCC and the combination of the two mechanisms allows for increased efficacy.

In addition to using monoclonal antibodies to target the specific cancer, it has recently been shown that disrupting the coinhibitory pathway can drive activation of TILs to target and eliminate the cancer cells. As mentioned above, cancer cells often alter the expression of ligands or receptors involved in the coinhibitory pathway, which then generates an immunosuppressive environment and allows the cancer cells to evade immune recognition and removal.  Therefore, if the coinhibitory pathway is blocked, then the immunosuppressive effect can be reversed.  Anti-CTLA4 antibodies were demonstrated to have this effect in animal models and quite rapidly were developed into therapeutic antibodies.  Anti-PDL1 and anti-PD1 have now also been developed into therapeutic antibodies.  All of these are currently being used to treat several cancers and being tested on many more types, with and without additional therapies. Due to the success of the current immune modulator therapies, it is likely this will continue to be a hot area for cancer research and development.

The third strategy that has recently been developed is using the recognition of specific cancer targets to recruit and induce T cell activation.  The goal has been to specifically target T cells to the cancer cells.  The approach has taken a couple of approaches.  One approach has been to develop a Chimeric Antigen Receptors (CAR) and express them in T cells.  A CAR is typically generated using the antibody specificity and linking it to signaling mechanisms that would induce the activation of the cell expressing it, typically T cells (CAR-T).  T cells typically generate reactivity through activation of the TCR through antigen presentation. However, cancer cells may either evade this response by either inhibiting T cells or limiting antigen presentation.  Remember that the cancer cells originate from the host and maintain most of the host composition and may not be seen as foreign by the immune system.  Therefore, if the T cell expresses a CAR that will target the cancer cell and once engaged activate the T cell the CAR-T cell can be specifically directed to the cancer without requiring antigen presentation by the cancer cell.  A modified version of this approach is to use a bispecific antibody (there are several approaches that accomplish this) to link the cancer and the T cell.  One end of the bispecific antibody recognizes a cancer specific target and the other end recognizes a T cell specific target.  This would lead to the targeting of T cells to the cancer.  In addition to targeting the T cells, the T cell specific recognition also activates the T cell (for example by using CD3 as the target), which will then lead to the T cell inducing a response towards the targeted cancer cell, again without the need for antigen presentation of the T cell.

All three of these strategies modulate immune responses to drive specific recognition of the cancer cells as well as immunologically target and kill the tumor. While some great successes have already been demonstrated it is clear that new developments will improve the specificity and efficacy of using one’s own immune system to fight cancer.

At MBS, as a custom antibody CRO, we are pleased to have the opportunity to work with many companies that are developing cancer therapeutics and diagnostics.  Whether it is the development of cancer therapeutics, anti-idiotypes for clinical assessment of therapeutics, cancer diagnostics, or antibodies for research, we would be pleased to discuss your future projects and needs for polyclonal or monoclonal antibody development

ABOUT DR. PELSUE

Dr. Pelsue joined MBS as Science Director after 20 years experience in Immunology research.  Dr. Pelsue is providing technical expertise and leadership to address challenging new antibody targets on behalf of our client base.