While cancer has been around for decades, the fight for survival and treatment options are still very top of mind. Treatment is simply playing catch up. We continue to try and get rid of the disease that has already infiltrated one’s body rather than catching it before it develops. We need to shift the focus from therapeutics that fight the disease to ways we can catch it before the deterioration in one’s body begins.
The current state of cancer treatments
When a patient has suspected cancer, a diagnosis must be confirmed or eliminated ASAP. It all begins with a thorough history and physical examination followed by diagnostic testing consisting of imaging, laboratory tests, and tissue biopsy. Once malignancy is confirmed and staged, treatment must begin urgently.
Whether the cancer is found in a solid or liquid tumor, histopathology and the stage of disease significantly impact prognosis and how the cancer is treated – with surgery, radiation, or systemic therapies. All these therapies have become more and more refined, novel, personalized, and targeted in their quest to eradicate the cancer, which translates to increased life expectancy, quality of life, and better patient outcomes. However, with this rapid innovation health care costs have continued to rise. Time, technology, innovation, and clinical trials yielding evidence-based data have evolved all types of treatments to become more targeted, subsequently reducing the amount of toxins spread throughout the body.
Surgery has evolved from surgical resections using only a scalpel to much more minimally invasive tissue sparing and conserving targeted procedures aided by new surgical tools from lasers to robots. Radiation, which once used wide portals to cover fields of disease, can now be achieved with newer targeted technology such as stereotactic radiosurgery and protons. Systemic therapies have also evolved to use more targeted approaches. For example, chemotherapy doses are reduced or omitted entirely from combination regimens. Small molecules, biologics, and cellular therapies, specifically designed and directed at tumor molecular targets, have been some of the greatest advances in oncology to date. Beginning with the revolutionary introduction of imatinib to treat chronic myelogenous leukemia (CML) and trastuzumab to treat HER2-positive breast cancer in the 1990s, to the most recent advances in designer CAR-T and bispecific antibodies, science and medicine will never stop advancing to conquer this most formidable enemy.
New cancer diagnosis techniques
Though we have made great advances and achievements in understanding the biomolecular and cellular pathophysiology of human diseases, so much is still left to learn and achieve in cancer diagnosis and treatment. The complexity of a tumor is still being understood, and targeted therapies alone and in combination are still yielding data from trials. The discovery engine in the biopharmaceutical industry is in full gear, leaving no shortage of possibilities to advance the field beyond its current state. Molecular tools for personalized genomic analysis and profiling the alterations in the tumor have now become mainstream. This allows for the upfront screening and enrichment of patients for clinical trials, enabling more robust readouts and analysis, faster therapeutic approvals, and the ability to get patient-verified therapies to patients optimally.
The next stage of cancer treatment: antibodies
While many focus on non-specific immunotherapies like checkpoint inhibitors, anti-PD-1 antibodies, and anti-PD-L1 antibodies, these antibodies are not targeted to the tumor but the entire immune system. These can cause adverse inflammatory effects such as colitis and myasthenia gravis. On the other hand, CAR-T cells are engineered to target the tumor but require complex cellular engineering of a patient’s own cells. Another class of cancer immunotherapies, multi-specific T cell engagers (TCEs), show promise in overcoming the limitation of checkpoint inhibitors and CAR-T cells.
Among the many crucial physiological roles that T cells play is cancer immunosurveillance. In this role, T cells scan normal tissues looking for and killing neoplasia. However, tumors can evolve several evasion mechanisms to avoid being killed by T cell-mediated cancer immunosurveillance, including reducing expression of the MHC class I molecules required for T cell recognition and killing of tumor cells, and upregulation of checkpoint inhibitors. TCEs can overcome these processes by serving as a bridge between T cell and tumor, even in the absence of MHC class I expression, and can help activate T cells to overcome checkpoint inhibition. Unlike checkpoint inhibitors, TCEs target the tumor specifically, which would be predicted to have less of a systemic effect on the immune system than checkpoint inhibitors. Unlike the tumor-specific CAR-T cells, TCEs don’t require complex cellular engineering and are easier to dose.
Although TCEs show great promise, only blinatumomab, a CD19-CD3 bispecific antibody that targets acute lymphoblastic leukemia, has achieved regulatory approval. The major difficulties with the development of TCEs, in general, have been toxicity concerns, short half-life requiring frequent dosing, and difficulty in targeting solid tumors.
As the challenges continue with TCEs, a new T cell engaging platform has been designed to address these concerns. The first key is target selection. The ideal target for a TCE is a tumor antigen that only exists on the tumor but has not been found in any normal adult tissue, thus, sparing off-tumor activity and potential toxicities. While these targets are rare, they include GPC3, which is an oncofetal antigen only expressed in hepatocellular carcinoma (HCC) in adults. By targeting GPC3, this TCE will directly target HCC, sparing on-target, off-tumor toxicities. Similarly, claudin 18.2, a stomach-specific isoform of the tight-junction-associated protein claudin 18, is also expressed in gastric cancer. While claudin 18.2 is expressed in normal gastric tissue and gastric cancer, the regenerative nature of gastric tissue suggests that this tissue may tolerate minor, recoverable toxicities while dosing with a TCE.
While selecting a cancer-specific target is ideal, this is not always possible with many cancers. For example, HER2 is a protein that is overexpressed in a wide range of cancers, including breast, ovarian, and gastric cancer. However, lower levels of HER2 are found on many normal tissues, which complicates tumor-specific targeting. Unlike that of many competitors, the new TCE platform features two tumor-antigen binding arms, which allow for reducing the strength of the binding to the tumor antigen to take advantage of avidity interactions (the cumulative effect of multiple binding affinities) to restrict the activity of our HER2-specific TCE ABP-102 to tumors that express high levels of HER2, sparing normal tissue with lower levels of HER2.
The major toxicity observed with T cell engagers is increased cytokine production, resulting in cytokine release syndrome (CRS), a potentially fatal cascade of cytokine production with symptoms reminiscent of septic shock, fever, and hypotension. CRA is a complex phenomenon but can be initiated by excessive or inappropriate T cell activation. The danger of CRS induced by T cell targeting agents is highlighted by the phase 1 clinical trial of the anti-CD28 antibody, theralizumab, in which all six participants suffered from severe CRS that required hospitalization, with at least four of the participants suffering multiple organ dysfunction. As a result, caution must be taken when targeting T cells. The proposed TCE platform provides an advantage over existing TCE platforms. To reduce the risk of CRS, many TCEs utilize only one binding arm for CD3, reducing the strength of binding to T cells and therefore reducing T cell activation. However, the TCEs that are monovalent for CD3 are often quite small (e.g., BiTEs), which reduces half-life and necessitates frequent dosing, or are full-size IgG-like molecules, but have asymmetrical heavy and light chains, complicating expression, and large-scale production. The developing TCE format, which features a full-sized IgG-like molecule for long half-life and while bivalent for CD3, is “functionally monovalent.” That is, the TCEs activate T cells similarly to CD3-monovalent TCEs, but feature completely symmetrical heavy and light chains, streamlining expression and large-scale production.
In addition to the challenges that TCEs face with respect to toxicity and frequency of dosing, efficacy against solid tumors is a problem. In fact, the only approved TCE, blinatumomab, targets hematological tumors. The tumor environment is often very difficult for antibody-based therapeutics to have an effect. Preclinical evidence suggests that this TCE format is superior to competitors’ format in promoting T cell infiltration into the tumor, leading to superior anti-tumor efficacy.
Taken together, the new TCE platform is designed to address the major challenges facing TCEs—toxicity, short half-life, and manufacturing challenges. In addition, the modular nature of the TCE platform allows for easy replacement of the tumor antigen and T cell binding regions to target other tumor antigens and T cell targets other than CD3, resulting in the possibility of treating an indefinite range of cancers.
These breakthroughs in T cells have provided an improved treatment method and overall better patient experience. This form of treatment is less invasive than traditional forms, such as chemotherapy, and reduces many side effects, including hair loss and nausea.
Importance of targeted therapies
The new technology being developed, including early cancer detection and treatment, gives physicians the power to go forth and be able to find and treat cancer more efficiently than ever before. As a society, particularly in the United States, we have made a lot of progress in using novel tools to treat cancer.
Since President Nixon declared war on cancer in 1971, and despite some great victories and many losses, there continues to be a never-ending battle in this long-fought war that seems never-ending. The convergence of great intellect and resources of academia and industry, fueled by continued entrepreneurship and investment funding into the biotechnology sector, despite the many risks of failure and expense, is one that is obvious to yield the greatest rewards to both prosperity and health. Ultimately, targeted therapies will improve lifespans and quality of life for cancer patients.
Eugene Chan is a health care executive.
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