IMMUNOTHERAPY RESEARCH - The Shift Toward Combination Therapies

INTRODUCTION

Traditional cancer treatments, such as radiotherapy and chemotherapy, are effective at treating many different types of cancer and remain the backbone of current therapy. However, they can be aggressive, are associated with serious side effects, and are vulnerable to treatment resistance. Improved understanding of cancer pathogenesis has given rise to new treatment options, including cancer immunotherapy, which takes a more targeted approach.

Immunotherapy focuses on the ability of an individual patient’s immune system to eliminate or control cancer. Immunotherapy in combination with traditional treatments has the potential for becoming a more effective alternative to the current standard of care. These types of combination therapies are currently under investigation and appear to have synergistic effects compared to the use of one therapy alone and produce more durable results.

Combination therapies require further research and the development of new immunotherapeutics, as well as new treatment plans. Currently, there is an unmet need for improved preclinical models, with functional immunity, to drive forward immunotherapy research in oncology and to enable the successful transition of immunotherapeutics from the laboratory to the clinic. The use of appropriate research models can accelerate new compounds to clinical trials or help repositioning existing compounds. This could enable the identification of the right patient population for each new drug before they are tested in the clinic, reducing high attrition rates. At the same time, preclinical models can be used to test different treatment strategies, often involving more than one agent, and select the most appropriate regimen to drive forward, improving patient comfort and saving lives.

TRADITIONAL CANCER THERAPY

Chemotherapy and radiotherapy kill rapidly dividing cells, preventing the growth of a tumor, but they may also affect healthy cells within the patient’s body. Most tissues have a reserve of pluripotent cells that are able to reactivate and start dividing and differentiate to replenish damaged or old cells. These cells, much like cancer cells are targeted by chemotherapy and radiotherapy and are not exempt from being damaged, causing severe side effects. Moreover, patients treated by traditional systemic chemotherapy as well as radiotherapy are prone to developing resistance in a fashion that is highly dependent on the tumor cell type, with some tumor being highly chemo- or radio-resistant. Traditional preclinical irradiation studies utilize simple single-beam techniques or whole body irradiation with lead shielding to focus the radiation to a specific area. However, the lead shielding does not ensure 100% protection to the tissues surrounding the tumor, and damage may occur. These settings no longer mimic treatment in the clinic as the dose or irradiation is much higher compared to what is given to the patient. A more sophisticated preclinical platform is now available, the image guided micro-irradiation (IGMI), to ensure a more targeted treatment with limited damage to surrounding healthy tissue and to reproduce in the lab with higher fidelity the clinical protocols.

IMMUNOTHERAPY

The ideal treatment for any disease is one that can cure or prevent it from spreading with minimal impact on the patient’s quality of life. Taking advantage of the immune system to fight cancer through the stimulation of a robust immune-based anticancer response by vaccination, or by attempting to inhibit factors that are currently blocking that response is showing promising results. Only in recent years, with a better understanding of the mechanism of action of immune cells, has progress started to be made in the application of immunotherapy to cancer patients, reducing side effects while increasing the efficacy of administered active compounds.

Currently, further research and new immunotherapeutics are needed before immunotherapy becomes a treatment accessible to all cancer patients. But with up to 95% of cancer drugs tested in Phase I trials not reaching a marketing authorization, the development of new drugs is costly and inefficient.¹ The application of immunotherapy as a first-line treatment is still surrounded by few regulatory issues, the most palpable being the need to justify the higher costs of immunotherapies versus other therapies. Moreover, it still remains to be understood why some patients and tumor types do not respond to immunotherapy, hence there is a pressing need to discover novel biomarkers to predict response. Current clinical studies are addressing the possibility of combining immunotherapeutic agents with other therapies, such as targeted agents, to btain more durable responses and avoid patients relapse.

The discovery of crucial molecular pathways that promote tumor growth and maintenance together with the development of drugs that specifically inhibit these pathways has ushered in a new era of cancer medicine. Antibody therapies, such as the anti-PD-1, anti-CTLA-4, and anti-PD-L1 antibodies, are currently the most successful form of immunotherapy.² Programmed Cell Death 1 (PD-1), Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4), and Programmed Death-Ligand 1 (PD-L1) are endogenous proteins that naturally downregulate the immune cells to prevent autoimmune diseases. The use of an antibody that binds to these proteins prevents this negative feedback and has been exploited for keeping the immune system alert to fight cancer. Cell-based therapies, or “cancer vaccines” represent another branch of immunotherapy, involving the isolation of immune cells from a patient’s blood or tumors. The cells are activated, grown, and re-infused into the patient, where they are expected to mount an immune response against the tumor. This approach, known as adoptive cell transfer (ACT), has been restricted to small clinical trials so far; however, treatments using these engineered immune cells have generated some remarkable responses in patients with acute lymphoblastic leukemia (ALL) or lymphoma.

ACT building blocks are patient-derived T cells that have been modified in vitro (CAR T cells) to express chimeric antigen receptors (CAR). These are able to specifically recognize and bind tumors antigens, inducing tumor cell death.

Current research focused on optimizing this approach emphasizes effective tumor targeting with limited off-tumor toxicity, optimized cell manufacturing to improve efficacy, and modulation of the host or cell product to increase in vivo persistence.³

The combination of traditional treatment and immunotherapy has shown to exert an additive effect on tumor growth inhibition over single-agent therapy alone, and can increase the number of cancer-fighting immune cells in the tumor.

COMBINATION THERAPY

The vulnerability of current therapies to treatment resistance has resulted in a shift from mono-agent approaches to combination therapy.

Hitting one oncogenic driver at a time in cancer cells, where several regulatory networks are altered, allows them to escape treatment by rewiring to alternative pathways or acquiring additional mutations that confer insensitivity to treatment. Combination therapies target more than one signaling node at the time and often achieve more durable responses.

Moreover, recent advances and the availability of IGMI has resulted in more accurate targeting of patient tumors and sparing of normal tissue with an associated reduction in side effects. This opens up the opportunity for multiple combination strategies of chemo- and radiotherapy. Interestingly, although radiotherapy has long been thought to be immunosuppressant, a refinement of the irradiation protocols and the availability of more sophisticated technologies, such as the IGMI, has opened up the possibility of combining radio and immunotherapy. Radiotherapy alone is often not sufficient to trigger antitumor immune responses, especially in poorly immunogenic cancers. However, the combination of radiotherapy with immune modulators, such as the checkpoint inhibitors, may have the capability to escalate antitumor responses to a level that could suppress or eliminate cancer. Combination therapy approaches are currently under investigation for many cancer types, including prostate, breast, and lung.

An example of combination therapy is the recent approval by the European Commission of vemurafenib and cobimetinib as a treatment for patients with metastatic melanoma. In the study, 495 patients received either vemurafenib or a combination therapy. The progression-free survival with the combination was around 12 months versus 7 months for vemurafenib alone. After 17 months, 65% of patients receiving the combination remained alive compared to 50% for single-agent treatment. The overall survival was 22 months with the combination treatment and 17 months with vemurafenib alone, representing a 30% reduction in the risk of death.

The approval of this combination was described as an important milestone in the development of new treatments that can help patients with advanced melanoma. Clinical trials continue to assess vemurafenib with cobimetinib for patients with melanoma, including a Phase II study. Additionally, a Phase Ib study is exploring the combination with the PD-L1 inhibitor, atezolizumab.⁴

Combining hormone therapy with radiation can help some men with early stage prostate cancer live longer. In one study concerning radiotherapy and short-term androgen deprivation for localized prostate cancer, the health status of nearly 2,000 men with low- and intermediate-risk prostate cancer were monitored. The 10-year survival rate for men who received the combination therapy was 62%, compared to 57% for men who received radiation therapy alone. Researchers also found that only 4% of the men who received combination therapy died of prostate cancer compared to 8% of those who received radiation alone.⁵

Alternatively, it has been found that, while treatment for non-small cell lung cancer uses a combination of two chemotherapeutics, adding a third drug does not add much benefit and is likely to cause more side effects. Single-drug chemotherapy is sometimes used for people who might not tolerate combination chemotherapy well, such as those in poor overall health or the elderly.⁶

MODELS

Efforts to maximize the benefits from immunotherapeutic agents are being limited by a distinct lack of experimental immunotherapy models that feature a functioning immune system. Developing effective immunotherapeutic drug treatments requires patient-relevant models with which to screen potential candidates. Moreover, due to the huge diversity and complexity of cancer, large collections of surrogate models are compulsory.

At present, the majority of experimental cancer models are composed of human tumors grown in immunocompromised mice. These are often derived from in vitro immortalized cancer cells, which allow researchers to follow the continuous evolution and malignancy of cancers and understand the biology of tumor development. These methods have been immensely helpful in studying how candidate compounds interfere with particular genetic mutations or pathways. But, immortalized cell lines are often selected based on their ability to grow, thus the debate over how well they represent a patient’s tumor that must engage in complex interactions with its environment in order to grow is always ongoing.

The ability to maintain and study immortalized cell lines in vivo has proved to be a valuable tool in cancer research for several decades. The most widely studied models have been cell line-derived xenografts (CDX). Both athymic nude mice and mouse xenograft models that use human tumor cell lines have been used to increase understanding of factors affecting tumor growth. As an integral step in oncology drug discovery process, CDX models provide key decision-making information and a biologically relevant platform, to study disease progression, develop novel therapies to improve treatment options, and allow an agent to move forward from preclinical trials.

Using patient-derived xenograft (PDX) models to perform human surrogate trials are at the forefront of targeted medicine research. Xenograft tumor models from patient-derived tumor tissue (PDTT), engrafted into immunocompromised mice, conserve original patient tumor characteristics, such as genotype, tumor vasculature, and architecture. This results in a model far more closely aligned with a patient’s disease, allowing the assessment of tumor evolution and response to therapy, the identification of the correct compound for each patient population before new drugs are tested and biomarker identification.

Both PDX and CDX are extremely useful tools for studying the physiopathology of human tumors and investigate the response to standard-of-care agents in a live host. But these models are just part of the solution to translating knowledge between clinical research and the clinic. To study the effects of immunotherapeutics, it is necessary for the host to have a functional immune system.

Syngeneic and Genetically Engineered Mouse Models (GEMM), with functional murine immunity, are available and widely used in immunotherapy research. Syngeneic models are mouse tumor cell lines growing in the same strain of mice in which the tumor originated, which provide an effective approach for studying how cancer therapies perform in the presence of a functional immune system. These models offer several undeniable advantages. They are relatively unexpensive, reproducible, and, unlike many current models, grow in immunocompetent hosts. As syngeneic tumor models have long been used in cancer research, there is a strong baseline of drug response data, and they come in a wide variety of tumor types. The models are also readily available, so studies are easily conducted with statistically meaningful numbers of mice per group.

Using these models in preclinical trials allows researchers to determine the effectiveness of combination therapies involving traditional cancer treatment and immunotherapy while mimicking human disease.

SUMMARY

There is a current need for preclinical tools that can significantly improve the qualification of candidates at a much earlier stage in the drug discovery process. PDX, CDX, GEMM, and syngeneic models can all contribute by offering a unique opportunity to study immunotherapy within a human tumor microenvironment, helping to move the most promising anticancer compounds to the clinic and reducing drug attrition rates by selecting the best clinical strategy.

These models are driving immunotherapy research, which reduces off-target side effects and allows treatment responses to last longer by inducing immune cells memory. The use of immunotherapy in combination treatment has provided promising results, improving the effects of traditional treatments alone and reducing treatment resistance. With the right models, preclinical trials can move faster, attrition rates can be the lowered, and the process of drug development can be cheaper and more efficient.

Immunology is forever seeking new and improved ways to offer patients an improved quality of life and the end goal potential cures. Models can potentially transform cancer treatment and perhaps provide cures for cancer forms that historically had very poor survival rates. Combining immunology with anticancer agents solves the challenge of drug resistance and enables a stronger anticancer effect.

REFERENCES

1. Wery, JP. Immunotherapeutics: the coming of age of cancer immunotherapy as a treatment paradigm. Therapeutics. 2015:9-14.
2. Callahan MK, Wolchok JD. At the Bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J Leukocyte Biol. 2013;94(1):41-53.
3. Lee DW, et al. The future is now: chimeric antigen receptors as new targeted therapies for childhood cancer. CCR Focus. 2012;18(10):2780-2785.
4. Broderick, JM. European Commission Approves Vemurafenib/Cobimetinib Combo for Melanoma. OncLive. 2015.
5. Jones CU, et al. Radiotherapy and short-term androgen deprivation for localised prostate cancer. NEJM. 2011;365(2):107-118.
6. American Cancer Society. Targeted therapies for non-small cell lung cancer. Available from: www.cancer.org/cancer. November 2015.

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Dr. Jean Pierre Wery, prior to joining CrownBio, was Chief Scientific Officer at Monarch Life Sciences, a company dedicated to the discovery and development of protein biomarkers. Prior to joining Monarch, he spent 3 years at Vitae Pharmaceuticals, Inc., where he was VP of Computational Drug Discovery. Before joining Vitae, he worked for 12 years at Eli Lilly and Company in various scientific and management positions. Dr. Wery earned his BS and PhD in Physics from the Uinversity of Liege, Belgium. Following his PhD, he completed post-doctoral studies at Purdue University with Prof. Jack Johnson. Dr. Wery has authored more than 50 abstracts and publications.