Lisa A. Raedler, PhD, RPh

Leaders of Roswell Park Cancer Institute (RPCI) in Buffalo, New York, have agreed to collaborate with the Center for Molecular Immunology (CIM) in Cuba to evaluate a therapeutic anticancer vaccine for nonsmall cell lung cancer (NSCLC) in the United States. Developed by CIM, the novel therapyCIMAvax EGF&mdash;is designed to deprive tumors of epidermal grown factor (EGF) by making this protein immunogenic and eliciting an immune response that depletes circulating EGF from the patient.

Targeting EGF protein represents a unique approach compared with today&rsquo;s treatments for advanced NSCLC. Agents that target EGF receptors (EGFR), such as small molecule inhibitors, are standard options for patients diagnosed with advanced NSCLC whose tumor cells express specific EGFR mutations. Several tyrosine kinase inhibitorserlotinib, gefitinib, and afatinib&mdash;have demonstrated the ability to block EGFR signaling and short-circuit cancer cell growth. These medications reduce the risk of NSCLC progression and death compared with placebo or chemotherapy, and are approved by the US Food and Drug Administration (FDA) for selected patients with advanced NSCLC.

Cuban researchers have learned that, in addition to directly inhibiting EGFR, cancer cell proliferation and invasion signaling can be interrupted by reducing the amount of EGF that can interact with EGFR.

Since 1995, Cuban researchers have been developing CIMAvax EGF, a parenteral (intramuscular) vaccine immunotherapy that deprives cancer cells of EGF.

They call this &lsquo;EGF castration.&rsquo; Their efforts have shown that manipulating the immune system to produce and release antibodies against EGF can shrink tumors and prevent cancer progression.

To date, CIMAvax EGF has undergone five phase I/II trials, a randomized phase II trial, and a recently completed a randomized phase III trial. Results of the phase I and II investigations compelled the Government Center for Quality Control of Medicines (CECMED), the Cuban regulatory authority, to license the CIMAvax EGF vaccine for use in adult patients with stage IIIB/IV NSCLC.

RPCI has partnered with CIM through academic and preclinical research exchanges since 2011. The agreement between CIM and RPCI to develop CIMAvax EGF in the United States was reached during the New York State Trade Mission to Cuba, which occurred in April. This was the first governor-led state trade mission to Cuba since President Obama began a process to normalize diplomatic relations between the United States and Cuba. The CIMAvax EGF agreement allows US testing of the CIM-developed vaccine for NSCLC, starting with early-phase clinical trials in patients with advanced stages of disease.

Candace S. Johnson, PhD, president and chief executive officer of RPCI and Wallace Family Chair in Immunology, and Kelvin C. Lee, MD, Jacobs Family Chair in Immunology at RPCI, represented the organization during the trip to Cuba at which the CIMAvaxEGF agreement was cemented. During an interview, Lee stated, &ldquo;We at Roswell Park are thrilled to have the opportunity to evaluate this therapeutic vaccine in US patients. It represents a completely new approach to treating NSCLC and has the potential for clinical benefit in earlier stages of NSCLC, possibly even in the prevention of lung cancer, as well as in the treatment of other solid tumors.&rdquo;

Use of immunotherapy for the management of advanced NSCLC received significant attention during the April 2015 meeting of the American Association of Cancer Research (AACR) in Philadelphia. Programmed death 1 (PD-1) receptor-blocking antibodies, including nivolumab

demonstrated impressive efficacy outcomes and tolerability in specific subsets of patients with advanced NSCLC. Nivolumab is indicated for use in patients with squamous NSCLC whose disease progressed on or after platinum-based chemotherapy.

Lee explained that CIMAvax EGF and checkpoint inhibitors such as nivolumab and pembrolizumab represent distinctly different immunotherapeutic approaches in advanced NSCLC. &ldquo;While the checkpoint inhibitors are attempting to unmask a T-cell immune response directly targeting the cancer cells, CIMAvax EGF is indirectly targeting the cancer by going after the growth factor the cancer needs to grow and survive. This indirect effect, along with very little toxicity seen in the CIMAvax EGF clinical trials, makes CIMAvax EGF an especially attractive option for cancer prevention, for example, in high-risk smokers or [in] patients at high risk to relapse with a second lung cancer. This cannot be done with current checkpoint inhibitors due to their side effects,&rdquo; Lee said.

One of the most compelling features of CIMAvax EGF is its safety profile. In the 80-patient, randomized, phase II clinical trial conducted in Cuba, no grade 3 or 4 treatment-related adverse events (AEs) were detected among the 40 patients receiving CIMAvaxEGF (per National Cancer Institute Common Toxicity Criteria version 3.0).

The most frequent grade 1 and 2 AEs were fever (25%), asthenia (20%), headache (25%), chills (18%), tremor (18%), and pain at the injection site (13%).

The vaccine&rsquo;s tolerability in the phase II trial, combined with data showing improved overall survival (OS) in recipients of CIMAvax EGF compared with control patients, led CIM and RPCI oncologists to hypothesize that CIMAvax EGF may have value in multiple other settings: in earlier stages of NSCLC, in prevention of lung cancer in high-risk patients, and in other solid tumors in which levels of circulating autologous EGF are high. RPCI investigators will be exploring these and other clinical research initiatives with their partners at CIM.

This phase III clinical trial of CIMAvax EGF has been under way since June 2006 at 18 clinical research sites in Cuba. A total of 579 patients with advanced (stage IIIB/IV) NSCLC were recruited, with a 2:1 randomization (2 treated patients for every control patient). Based on phase II study findings, efficacy outcomes of the phase III study will be subanalyzed per patient age (>60 years and &le;60 years).

According to Lee, &ldquo;Worldwide, more than 5000 patients have been safely treated with CIMAvax EGF. What is especially appealing is that the cost of CIMAvax EGF is very low, so that it can be used even in locations where resources are limited. It is administered monthly via four intramuscular injections that can be administered by primary care physicians (as it is being done in Cuba) or other health care providers, such as pharmacists or nurse practitioners. These features, combined with an OS benefit, make it appropriate to think about applications in many clinical circumstances, and to prioritize use of CIMAvax EGF for patients living in communities with little or no access to tertiary medical care.&rdquo;

RPCI representatives estimate that RPCI-sponsored trials of CIMAvax EGF will be open for US patient enrollment by the second quarter of 2016.

1. Rodr&iacute;guez PC, Rodr&iacute;guez G, Gonz&aacute;lez G, Lage A. Clinical development and perspectives of CIMAvax EGF, Cuban vaccine for non-small-cell lung cancer therapy.

2. Gonz&aacute;lez G, S&aacute;nchez B, Su&aacute;rez E, et al. Induction of immune recognition of self-epidermal growth factor (EGF): effect on EGF biodistribution and tumor growth.

3. Opdivo (nivolumab) package insert. March 2015. http://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed May 2, 2015.

4. Merck seeks expanded approval of Keytruda immunotherapy to treat lung cancer. http://www.thestreet.com/story/13117202/1/merck-seeks-expanded-approval-of-keytruda-immunotherapy-to-treat-lung-cancer.html. Accessed May 2, 2015.

Articles

Leaders of Roswell Park Cancer Institute (RPCI) in Buffalo, New York, have agreed to collaborate with the Center for Molecular Immunology (CIM) in Cuba to evaluate a therapeutic anticancer vaccine for nonâ€“small cell lung cancer (NSCLC) in the United States.

US-Cuban Partnership Developing Anticancer Vaccine for NSCLC

Blocking activin-A, a protein that is secreted by non-small cell lung cancer (NSCLC) cells, may prevent cancer metastasis, according to research conducted at the University of Virginia (UVA). Scientists there discovered that activin-A is overexpressed in human NSCLC tissue samples and that, in laboratory studies, blocking this protein prevented metastasis of these lung cancer cells.

This discovery has important implications for drug development, as well as for staging and monitoring of patients with NSCLC.

During metastasis, tumor cells travel from the site of the original tumor to other places in the body. It is at this stage that cancer is most lethal. Despite breakthrough discoveries of novel drug targets and the evolution toward personalized medicine in cancer care, management of patients with metastatic cancer remains one of the toughest challenges for today&rsquo;s clinicians.

Researcher Stefan Bekiranov, PhD, of the UVA department of biochemistry and molecular genetics and the UVA Cancer Center, explained, &ldquo;To be able to detect metastasis when it is happening would be extremely important; it is one of the major processes that kills cancer patients. Today, studying and diagnosing cancer metastasis are challenging; the process is very transient. We do not have good markers to learn that it has begun.&rdquo;

Translational cancer researchers have focused significant resources on the identification of relevant mutations and other genetic changes, as well as signaling pathways that contribute to cancer progression. In contrast, Bekiranov believes that research focused on tumor metastasis, including how cancer cells travel to new locations and specific factors that influence this process, remains untapped. He and his colleagues at UVA have taken a key step in documenting how tumor cells work in concert with various components of their microenvironment, including growth factors, such as transforming growth factor-&beta; (TGF-&szlig;), which initiate metastasis. Cancer cells maintain the drive toward the metastatic state by upregulating and secreting their own growth factor, activin-A, which is a TGF-&szlig; superfamily member. Activin-A was initially discovered in the 1980s. First observed to stimulate biosynthesis and secretion of follicle-stimulating hormone from pituitary gonadotropes, activin-A was thought to be a reproductive hormone. Today, it is clear that this protein has a multitude of functions and is relevant in a variety of disease states, including cancer. Activin-A is understood to affect cell proliferation, differentiation, and apoptosis; homeostasis; metabolism; and endocrine function; as well as immune response, wound repair, and inflammation.

Data from the laboratory studies performed by Bekiranov et al at UVA, which were published in the January 15, 2015, issue of

, showed that activin-A and other soluble growth factors are secreted by tumor cells during a critical step in NSCLC tumorigenesis, the induction of epithelial-to-mesenchymal transition (EMT).

In humans, EMT and its reverse process, mesenchymal-epithelial transition (MET), are important in embryonic growth, fibrosis development, wound healing, and the evolution of cancer. Because mesenchymal cells can enter the bloodstream, induction of EMT enables cancer cell invasion and metastases. Mesenchymal cells also resist apoptotic signaling, upregulate genes to promote self-renewal, and display properties of cancer-initiating cells (CIC). A sizable body of literature implicates CICs in tumor onset, maintenance, mutation accumulation, and metastasis. After conducting multiple laboratory experiments with both nonsquamous and squamous NSCLC cell lines, UVA scientists concluded that activin-A is critical to the maintenance of mesenchymal properties of CICs and promotes metastasis in NSCLC.

A cancer cell&rsquo;s ability to maintain mesenchymal properties may also be relevant in early-stage cancers. Bekiranov explained, &ldquo;What is sometimes underappreciated is the importance of EMT as a mechanism of resistance in the primary tumor environment. We believe EMT is critical in both local tumor growth and the metastatic setting. Primary cancer cells resist drug therapy not just through driver mutations or adaptive signaling. A potentially major mechanism by which primary tumors develop resistance is the transition to the mesenchymal state.&rdquo;

Pharmaceutical researchers may be able to exploit the growing body of knowledge regarding activin-A to develop inhibitors of metastatic spread. Bekiranov believes that activin-A represents a target that can be affected by drugs.

&ldquo;Developing a more specific analog of today&rsquo;s activin-A inhibitors will be the first step. Such a drug has immense potential, which was one of the major points of our study. Our mechanistic experiments showed that activin-A is required for NSCLC cells to maintain their mesenchymal state. All the way through the process of cell transition, cells depend on activin-A. Drugs that block activin-A could be important in treating metastatic NSCLC, as well as cells that have undergone EMT in the primary tumor,&rdquo; Bekiranov said.

Cancer is most lethal after it has metastasized. Identifying and targeting biologic determinants of cancer cell spread may prevent the process and enhance patient outcomes.

Cancer scientists at UVA have observed that activin-A is critical to the maintenance of mesenchymal properties of NSCLC cells, and regulates the metastasis of these cells in laboratory studies.

After blocking activin-A expression in laboratory models, NSCLC cells grew and formed a primary tumor, but did not metastasize.

These discoveries may influence the development of cancer-specific activin-A inhibitors, as well as blood-based biomarkers for patients with NSCLC and other solid tumors.

In addition to prompting drug development, the UVA discoveries also suggest that activin-A might have value as a biomarker. Using a simple blood test, clinicians who are monitoring patients with localized NSCLC may be able to identify that the metastatic process has begun, before obtaining imaging evidence or the emergence of symptoms.

For patients with early-stage disease, high levels of activin-A might also assist clinicians in therapy selection.

&ldquo;When cancer cells transition to the mesenchymal state, unfortunately, they tend to resist today&rsquo;s therapeutics that target proliferative pathways, such as the MAP kinase pathway. If you learn that activin-A levels are high for a patient, you might approach the treatment differently. You would want to use one drug that targets primary tumor cells in the epithelial state, and another that targets cells in the mesenchymal state,&rdquo; Bekiranov explained.

Wamsley JJ, Kumar M, Allison DF, et al. Activin upregulation by NF-&kappa;B is required to maintain mesenchymal features of cancer stem-like cells in non-small cell lung cancer.

Chen YG, Wang Q, Lin SL, et al. Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis.

Sulyok S, Wankell M, Alzheimer C, Werner S. Activin: an important regulator of wound repair, fibrosis, and neuroprotection.

Robson NC, Wei H, McAlpine T, Kirkpatrick N, Cebon J, Maraskovsky E. Activin-A attenuates several human natural killer cell functions.

Blocking activin-A, a protein that is secreted by non-small cell lung cancer (NSCLC) cells, may prevent cancer metastasis, according to research conducted at the University of Virginia (UVA).

Lisa A. Raedler, PhD, RPh | Authors

Articles

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