US-Cuban Partnership Developing Anticancer Vaccine for NSCLC

MOUSEOVER

Candace S. Johnson, PhD

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—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’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—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.¹Since 1995, Cuban researchers have been developing CIMAvax EGF, a parenteral (intramuscular) vaccine immunotherapy that deprives cancer cells of EGF.¹They call this ‘EGF castration.’ Their efforts have shown that manipulating the immune system to produce and release antibodies against EGF can shrink tumors and prevent cancer progression.^1,2

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.¹

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, “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.”

Kelvin C. Lee, MD

Kelvin C. Lee, MD

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 nivolumab³and pembrolizumab,⁴demonstrated 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.³Lee explained that CIMAvax EGF and checkpoint inhibitors such as nivolumab and pembrolizumab represent distinctly different immunotherapeutic approaches in advanced NSCLC. “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,” 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).¹The 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%).¹The vaccine’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 ≤60 years).¹

According to Lee, “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.”

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

References

1. Rodríguez PC, Rodríguez G, González G, Lage A. Clinical development and perspectives of CIMAvax EGF, Cuban vaccine for non-small-cell lung cancer therapy.MEDICC Rev. 2010;12(1):17-23.

2. González G, Sánchez B, Suárez E, et al. Induction of immune recognition of self-epidermal growth factor (EGF): effect on EGF biodistribution and tumor growth.Vac Res. 1996;5(4):233-244.

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.

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