Can Innate Immune Cells Engage in Anti-Tumor Activity?
By Myra L. Patchen, PhD
Although cancer immunotherapies have been around for decades, most of the various treatment approaches have not worked very well. However, with a fundamental shift in the variety of immunotherapeutic approaches now available, the possibility to engage both the innate and adaptive arms of the immune system to kill cancer cells exists.
Until recently, the focus of many of the most successful immunotherapies — monoclonal antibodies — has been to target cancer cells. Essentially, monoclonal antibodies compensate for the fact that the body often does not recognize cancer cells as a threat and therefore does not generate natural antibody-mediated immune responses against them. Once bound to their target, monoclonal antibodies do sometimes indirectly harness the body’s repertoire of immune cells to fight the cancer. But more often, they rely on directed actions such as blocking receptors on the cancer cells or preventing the ability of the tumor microenvironment to support the continued growth of the tumor. The issue with such an approach has been that monoclonal antibodies alone, while very successful commercially, have often brought relatively limited clinical benefit to the patient.
Traditionally, direct recruitment of the body’s immune cells in the fight against cancer has been a strategy more or less limited to cancer vaccines. These vaccines typically work through presenting cancer antigens to the adaptive immune system (either T-cells or B-cells, and sometimes both) in order to alert the immune system to the threat. However, this approach relies very heavily on the highly specific nature of the adaptive immune response and, as a result, has generally been met with limited efficacy to date.
The 2011 approval by the U.S. Food and Drug Administration of ipilimumab (Yervoy®), Bristol-Myers Squibbs’ first in class immune modulator for patients with advanced forms of melanoma, has changed this situation markedly. Yervoy is a monoclonal antibody, but rather than targeting the tumor, Yervoy targets the adaptive immune system, and in doing so, aims to unleash its killing power.
Yervoy blocks binding of the CTLA-4 receptor on cytotoxic T-cells. CTLA-4 is normally involved in down-regulating these important immune cells, which serves to minimize immune-mediated damage to healthy tissues. When Yervoy binds to CTLA-4, in essence, it “takes the brakes off” the cytotoxic T-cells so that they are able to more freely function and kill cancer cells. The key difference in the strategy employed by Yervoy is that it is modulating, and in this case derestricting, the immune system, essentially making it easier for the immune system to find and kill cancer cells. The activity of Yervoy is not specific to the cancer cell itself, but rather is mediated through modulating responses of T-cells against the cancer cells in general.
Although overall response rates with Yervoy in clinical trials were modest (~11%),1 it is the first melanoma drug to show substantial improvement in survival, yielding a median overall survival of greater than 10 months, with ~20% of patients surviving 3 years and 17% of patients surviving 7 years or beyond.1,2,3 Thus, Yervoy may extend survival in some patients by years, not just months or weeks, as is the case with most conventional cancer treatments for advanced disease.
By directly targeting and modulating the patient’s immune system, Yervoy has validated immune checkpoint blockade as a therapeutic paradigm, and new data for other immune modulating drug candidates presented at the 2013 American Society of Clinical Oncology (ASCO) meeting last June led many to believe that a new era in cancer medicine had begun.
The ASCO buzz focused on a new class of monoclonal antibodies targeting another T-cell receptor, this time the PD-1 receptor function, binding of which also negatively regulates immune responses and inhibits cytotoxic T-cell activity. Bristol-Myers Squibb reported an overall response rate of 31%, a median overall survival of 16.8 months, and a 3-year survival rate of 40% in stage IV melanoma patients treated with its anti-PD-1 drug, nivolumab,4 further exceeding effects of previous melanoma therapies.
Interim data for Merck’s anti-PD-1 drug, lambrolizumab, which is also being evaluated in patients with advanced melanoma, showed an impressive 52% overall response rate in the treatment arm receiving the highest dose.5 Both companies are conducting additional trials in a variety of cancers.
Although immune checkpoint blockers have garnered much recent attention, numerous other immunotherapy agents are also under investigation, with more than 30 such agents currently in Phase 3 clinical trials, according to the Cancer Research Institute.6
The potential of immunotherapies is difficult to overstate. Citigroup Global Markets (CGM) analysts believe that in a decade from now immunotherapy will be the “backbone” of treatment regimes for 60% of all cancer types. The potential revenue opportunity for the biopharmaceutical industry by 2023 is projected at more than $35 billion, according to a CGM report entitled, “Immunotherapy – The Beginning of the End for Cancer.”
Can Innate Immune Cells Engage in Anti-Tumor Activity? (continued)
The Sleeping Giant of Cancer Immunotherapy
Despite tremendous promise, most cancer immunotherapies, including the new classes directly modulating T-cell receptors, focus on harnessing the function of cells of the adaptive immune system. Historically, the conventional wisdom of the medical community is that only the adaptive immune system can be used to target cancer. However, the cellular stars of adaptive immunity – cytotoxic T-cells, CD4 T-cells and natural killer cells – account for less than 30% of the entire immune cell population.
The tumor microenvironment from an immune perspective is complex, but the question of whether immunotherapy can win the cancer battle may come down to a simple issue: numbers. Even if new immunotherapies can activate T-cells to attack the tumor, are there enough T-cells to overcome those cells in the tumor microenvironment that are working to suppress the effect?
The innate immune system is perhaps the sleeping giant of cancer immunotherapy. This arm of the immune system is the body’s first line of defense against invading pathogens such as bacteria, viruses and fungi. Although highly effective at killing infectious organisms, the innate immune system’s inability to distinguish cancer cells from other “self” cells has convinced most researchers that it has no role in oncology treatments.
In contrast to the adaptive immune system, the innate immune system relies on an entirely different set of effector cells, neutrophils and monocytes, that comprise about 65% of the body’s immune cell population – a formidable army of approximately 17 trillion cells.
One of the most successful immunotherapies for solid cancer is in bladder cancer, where a patient is administered weekly intravesical instillation of Bacillus Calmette Guerin (BCG).7 The BCG induces a strong local immune response within the bladder characterized by massive secretion of cytokines as well as inflammatory cellular infiltration. Recent research has demonstrated that the immune cells that mediate the anti-tumor activity are neutrophils.8 Is it possible to engage and redirect this much larger population of innate immune cells against other cancers?
Minnesota-based Biothera’s investigative drug, Imprime PGG®, is a new immunotherapy that, like Yervoy and the PD-1 monocolonal antibodies, targets the patient’s immune system rather than the cancer cells. However, Imprime PGG mobilizes and directs the much larger population of innate immune cells to recognize and kill cancer cells.
Imprime PGG binds directly to specific receptors on neutrophils and monocytes and modulates their function to partially activate the cells. This effectively raises the readiness of these cells but another trigger is required before they will recognize and kill cancer cells – the cancer cells have to be targeted, or “flagged”, by a complement-activating antibody. 9, 10, 11
Researchers hypothesized that administering Imprime PGG to cancer patients receiving anti-cancer monoclonal antibodies would redirect their innate immune cells to kill cancer cells as if they were killing invading pathogens. In short, Imprime PGG would bring this large population of innate immune cells into the fight against cancer.
Imprime PGG has been evaluated in multiple Phase 1 and 2 clinical trials in colorectal cancer (CRC), non-small lung cancer (NSCLC) and chronic lymphocytic leukemnia (CLL) and is currently under investigation in a Phase 3 CRC trial. In completed trials, substantial improvements in response rates versus historical or randomized controls were observed.12-14
Recently, Biothera announced top-line results from its randomized controlled Phase 2b clinical trial in NSCLC that evaluated the combination of Imprime PGG, cetuximab [Erbitux®, Bristol Myers-Squibb], and carboplatin/ paclitaxel compared with the cetuximab and chemotherapies alone.15
The primary endpoint of this open-label, multicenter, randomized trial in 90 patients with untreated advanced NSCLC was objective response rate (ORR). The combination of Imprime PGG with cetuximab and carboplatin/paclitaxel showed substantial and statistically significant improvement in ORR compared to the control group. Imprime PGG was also well tolerated, with adverse events consistent with toxicities attributable to the cetuximab or chemotherapy drugs alone.
The study’s ORR was improved further in the subset of subjects who tested positive for a biomarker linked to the ability of their innate immune cells to bind and respond to Imprime PGG. More importantly, a secondary endpoint of overall survival showed substantial improvement among biomarker-positive subjects.
Can Innate Immune Cells Engage in Anti-Tumor Activity? (continued)
Potential of Immunotherapies
There is little doubt that the hope for new and significantly improved cancer therapies is focused on immunotherapy. New immunotherapeutic approaches are demonstrating exciting results in the clinic. Long-term survival, the gold standard for all cancer therapies, may well rest in understanding how immunotherapies can be combined to shift the immune cell balance of power in the battle going on in the tumor microenvironment. Perhaps, it is a battle of numbers and the discovery of the ability to redirect the large populations of innate cells, like neutrophils and monocytes, to join the attack against cancer may markedly alter clinical outcomes.
By Myra Patchen, Ph.D., Chief Scientific Officer, Biothera
Biothera is biotechnology company that is developing a phase 3 cancer immunotherapy, Imprime PGG® for multiple indications, including colorectal cancer, non-small cell lung cancer, chronic lymphocytic leukemia and non-Hodgkin lymphoma. While other cancer immunotherapies elicit adaptive immune responses, Imprime PGG engages and redirects innate immune cells to kill antibody-targeted cancer cells.
1 Yervoy (ipililmumab) Package Insert; Highlights of Prescribing Information. Bristol-Myers Squibb. 2011.
2 Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. European Cancer Congress, 2013; Abstract LBA24; Presented September 28, 2013.
3 Hodi FS, O’Day SJ, McDermott DF. et al. Improved survival with ipilimumab in patients with metastatic melanoma. New Eng J Med. 2010; 363:711-723.
4 Sznol M, Kluger HM, Hodi FS, et al. Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538). J Clin Oncol. 2013; 31 (suppl; abstr CRA9006).
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8 Stuttmann H, Riemensberger J, Bebtien G, et al. Neutrophil granulocytes are required for effective Bacillus Calmette-Guerin immunotherapy of bladder cancer and orchestrate local immune responses. Cancer Research. 2006; 66:8250-8257.
9 Li B, Allendorf DJ, Hansen R, et al. Yeast beta-glucan amplifies phagocyte killing of iC3b-opsonized tumor cells via complement receptor 3-Syk-phosphatidylinositol 3-kinase pathway. J Immunol. 2006; 177:1661-1669.
10 Salvador C, Li B, Hansen R, et al. Yeast-derived beta-glucan augments the therapeutic efficacy mediated by anti-vascular endothelial growth factor monoclonal antibody in human carcinoma xenograft models. Clin Cancer Res., 2008; 14:1239-1247.
11 Qi C, Cai Y, Gunn L, et al. Differential pathways regulating innate and adaptive antitumor immune responses by particulate and soluble yeast-derived β-glucans. Blood. 2011; 117:6825-6836.
12 Tamayo, M.E., Cornelio, G.H., Bautista, J.B., Flores, M.L., Tioleco, P.S., Kurman, M.R., Vasilakos, J.V., Marsh, L.M., Gargano, M.A., Patchen, M.L. (2010) Safety and efficacy of Imprime PGG plus cetuximab with irinotecan and without irinotecan in patients with advanced colorectal cancer (CRC): A Phase 1b/2 study with KRAS subpopulation analysis. 12th European Society of Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer, Barcelona, Spain. Annals of Oncology. 21 (Suppl 6) (Abstract #PD0009).
13 Segal, N.H., Senzer, N., Gada, P., Marsh, L.M., Gargano, M.A., Patchen, M.L., Saltz L. (2011) Imprime PGG plus cetuximab therapy for advanced KRAS mutant colorectal cancer. 13th European Society of Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer, Barcelona, Spain. Annals of Oncology. 22 (Suppl 5) (Abstract #PD0013).
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15 Schneller, F., Thomas, M., Sadjadian, P., Kollmeier, J., Bose, N., Antonysamy, M., Patchen, M., Lowe, J., Mattson, P., Huhn, R. (2014) PGG β-glucan with carboplatin, paclitaxel and cetuximab for chemoimmunotherapy of advanced non-small cell lung cancer (NSCLC). European Society of Medical Oncology (ESMO) and 4th European Lung Cancer Conference (ELCC), Geneva, Switzerland, Abstract #100PD. J Thoracic Oncol. Vol 9 (Suppl 14), S40.