Abstract
Hepatic metastases from melanoma are usually associated with recurrence and short survival, even in patients with a solitary metastasis. Two patients, one with melanoma of unknown primary and one with ocular melanoma, underwent resection of a solitary liver metastasis followed by treatment with eltrapuldencel-T, a patient-specific therapeutic vaccine consisting of autologous dendritic cells loaded with antigens from irradiated melanoma cells obtained from an autologous tumor cell line. Following surgical resection, the ocular melanoma patient remained progression free for more than 4.5 years and was known to be alive more than 8.5 years later, while the other patient, who previously had experienced lung and small bowel metastases, has remained disease free and is alive more than 12 years later. These two cases illustrate how immunotherapies designed to induce immune responses to tumor-associated antigens (TAA), as opposed to releasing previously existing responses to TAA that have been suppressed, may also enhance long-term disease control and survival.
Background
Liver metastases from ocular or cutaneous melanomas are associated with an extremely poor prognosis. 1,2 A small proportion of such patients are considered to be suitable candidates for surgical resection of hepatic metastases. This subset of patients typically is in good medical condition and has a solitary metastasis, or a few metastases, limited to the liver and potentially completely resectable. However, even these patients are prone to recurrences in the liver and elsewhere, and subsequent death. In two large meta-analyses, patients whose melanoma liver metastases were resected had a median survival of about 2 years and a 5-year survival of about 25%. 3,4 Thus, an unmet need exists for a postoperative adjunctive therapy that may increase survival.
One such possible therapy is eltrapuldencel-T (CLBS20), a patient-specific vaccine consisting of autologous dendritic cells loaded with antigens from a self-renewing cell line of autologous tumor cells. 5 –8 In patients with stage 4 or recurrent stage 3 melanoma, this product was associated with a 73% 2-year survival in a single-arm trial, 6 and a 72% 2-year survival in a randomized phase 2 trial. 7 The only side-effects associated with this vaccine were mild local injection site reactions. Herein the authors describe impressive progression-free survival and long-term survival associated with the use if this patient-specific vaccine in two patients with liver metastases.
Case Presentations
Case report 1
A 56 year-old male was discovered to have a lung mass that was resected in March 2002 and found to be metastatic melanoma from a presumed unknown primary. One month later he enrolled in the double-blind CancerVax trial that compared an allogeneic tumor cell vaccine plus Bacillus Calmette–Guérin (BCG) to BCG alone in stage 4 melanoma patients who had been rendered disease free by surgery. 9 He completed the prescribed 1-year of treatment, but 1 month later, in May 2003, he was found to have a small bowel metastasis that was resected and used to establish an autologous tumor cell line. As per the CancerVax trial, he resumed treatment with the same agent, which eventually was disclosed to be BCG. Four months later, in November 2003, a solitary liver metastasis was detected radiographically, then surgically excised followed by intraoperative radiofrequency ablation to the area.
In December 2003, at age 58, he enrolled in an open-label, single-arm trial (Clinicaltrials.gov NCT00948480, registered July 28, 2009), in which eltrapuldencel-T was suspended in 500 μg of sargramostim (granulocyte-macrophage colony stimulating factor [GM-CSF]) and injected weekly for 3 weeks, then monthly for 5 months. 6 He underwent a leukapheresis to obtain mononuclear cells that were coincubated with his autologous tumor cell line to produce his patient-specific therapeutic vaccine. At the time of enrollment, he had no measurable disease, his Eastern Cooperative Oncology Group (ECOG) performance status was 0, a lactate dehydrogenase (LDH) was in the normal range, and he exhibited a positive reaction to a Candida skin test. He received all eight planned injections and experienced no significant toxicity related to the treatment. Before initiating this therapy, his longest progression-free intervals had been 14 months following resection of the lung metastasis, and then 6 months following resection of the small bowel metastasis. As of January 2016, he is known to be alive and remains disease free more than 12 years later, without having had any therapy other than eltrapuldencel-T.
Case report 2
A 50-year-old male had a biopsy diagnosis of left ocular melanoma in late October 2003. He was noted to have diffused scleral pigmentation attributed to congenital ocular melanocytosis that was presumed to also involve the uveal tract. In January 2004, he underwent an orbitotomy with excision of a tumor arising from the posterior aspect of the left eye with both intra- and extraorbital components. Three months later, he underwent 5 days of radioactive plaque therapy to what was felt to be residual melanoma. He then did well until January 2007 when imaging disclosed a 1.3 × 0.9 cm mass arising below and lateral to the optic nerve head. This area was treated with stereotactic radiation therapy followed by whole brain radiation therapy. Restaging identified a liver lesion that was biopsied and confirmed to be metastatic melanoma. In April 2007, he underwent wedge resection of the 1.8 cm hepatic metastasis. He was followed expectantly while efforts were made to establish an autologous tumor cell line for use as an investigational vaccine product.
In October 2007, at age 54, he was referred for treatment and randomized to receive eltrapuldencel-T as part of an open-label, randomized phase 2 clinical trial (Clinical trials.gov 00436930, registered February 15, 2007). 7 At the time of randomization, he had no measurable disease, his LDH level was in the normal range, and his ECOG score was 0. He was anergic to skin tests for Candida and trichophyton. He underwent a leukapheresis to obtain monocytes for conversion into dendritic cells, and from December 2007 to May 2008, he received all eight planned injections of vaccine suspended in 500 μg GM-CSF administered once a week for 3 weeks, and then once a month for 5 months. The treatment was well-tolerated.
The orbital mass remained stable, but did not regress; so, in September 2009, he underwent enucleation of the left eye with confirmation of multiple foci of residual melanoma. He remained disease free for more than 2 years. In October 2011, imaging disclosed what appeared to be multiple hepatic metastases and abdominal lymphadenopathy along the vena cava. Biopsies were nonconfirmatory, but he underwent two cycles of high-dose interleukin-2 (IL-2). He continued IL-2 for a total of 4 months. He had remained euthyroid following Hashimoto's thyroiditis many years earlier, but became hypothyroid while on IL-2. By August 2012, several hepatic lesions appeared to be enlarging; so, in September 2012, he underwent resection of 12 hepatic metastases and perihepatic lymph nodes that were confirmed to be melanoma; at least two hepatic metastases could not be resected. From March to October 2013, he was treated with nivolumab, but then was felt to have further progression. In the spring of 2014, he underwent radiation to the liver followed by four cycles of ipilimumab. In January of 2015, it was noted that his liver lesions had regressed. During the rest of 2015, he underwent radiation therapy to specific lesions and received additional doses of ipilimumab.
Discussion
These two patients were diagnosed with solitary hepatic metastasis after earlier diagnoses of melanoma. One had an ocular melanoma with clinical behavior typical of uveal melanoma and one had a melanoma of unknown primary with previous lung and small bowel metastases. In addition to having a solitary liver metastasis, they had in common aggressive local treatment of disease and being rendered disease free in the liver by surgery before being treated with their patient-specific therapeutic vaccine. One patient has been disease free for more than 12 years since his hepatic resection; the second patient was free of distant metastases for more than 4.5 years after undergoing resection of his liver metastasis. Both patients have survived more than 8.5 years from the original diagnosis of hepatic metastases.
The obvious question is whether these patients would have experienced such a long disease-free interval and overall survival after surgical resection of a solitary hepatic metastasis in the absence of the vaccine therapy? The literature suggests probably not. A large institutional review confirmed that, unfortunately, most patients with liver metastases are not candidates for surgical resection, typically because of the extent of intrahepatic or concurrent extrahepatic disease. 1 Therefore, between 1991 and 2010, only 58/1078 (5.4%) patients with liver metastases underwent resection and/or ablation. Most but not all patients had a solitary metastasis; so, the median number of lesions resected was 1 and the average resected was 1.8. Their median survival was 24.8 months and 30% survived 5 years. Survival was worse in patients whose disease could not be resected with clear margins. In one large meta-analysis, 551 patients who had undergone surgical resection of hepatic metastases, collected from 13 studies, had a median survival of 24 months and a 5-year survival rate of 24%. 3 In another meta-analysis, 579 patients collected from 22 studies had a median survival of about 24 months, a 5-year survival rate of about 23%, and median disease-free survivals that ranged from 8 to 23 months. 4 Based on these trials, the probability of 5-year survival in patients undergoing such resections is about 25%, and therefore, the probability that two consecutive patients would survive 5 years is estimated to be only about 6%. From their dates of hepatic metastasectomy, these two patients who were treated with adjuvant eltrapuldencel-T had progression-free survivals of greater than 4.5 years and greater than 12 years, and overall survival beyond 8.5 years. Of 72 patients who were treated with this product, they are the only two who began treatment following resection of a solitary liver metastasis.
Historically, melanoma liver metastases have been considered an especially ominous finding, and they are especially common in certain uveal cancers. 10 For this reason, many trials have specifically excluded patients with metastatic ocular melanoma. Although the ocular melanoma patient reported here was not cured with the adjunctive therapeutic vaccine, he still experienced no new sites of progressive disease for more than 4.5 years after resection of his liver metastasis and has survived more than 8.5 years since the hepatic metastasectomy. Median disease-free survival following hepatic metastasectomy in ocular melanoma patients is only about 9 months, and median survival is only about 30 months. 2 The patient reported here subsequently derived clinical benefit from other immunotherapies. It is possible that these immunotherapies were effective, in part, because of immune responses previously induced by the vaccine to patient-specific neoantigens. In a retrospective review of single-institutional data, it was found that patients treated with IL-2 (IL-2), who had been treated with a patient-specific vaccine either before or after high-dose IL-2, had a much higher rate of 5-year survival than patients treated with high-dose IL-2 alone. 11
Theoretically, this patient-specific vaccine takes advantage of the autologous nature of the tumor cells and the purity of the tumor cells, 12 as well as the hundreds to thousands of tumor-associated antigens (TAA), including patient-specific neoantigens that are potentially presented in the vaccine. 13 This may be an effective way to target tumor stem cells. 14 This approach also takes advantage of ex vivo loading of dendritic cells and presentation of antigens by dendritic cells, which in a randomized trial in patients with metastatic melanoma was associated with better survival than injection of irradiated tumor cells. 7 In the randomized phase 2 trial, changes in serum cytokines from samples obtained 1 week before and 1 week after three weekly injections were differed markedly for patients treated with eltrapuldencel-T compared to those vaccinated with irradiated tumor cells. 15
The role of therapeutic cancer vaccines has been questioned in the current era with the availability of anti-BRAF/anti-MEK and anticheckpoint antibodies. 16,17 In the past few years, there have been remarkable advances in the treatment of metastatic melanoma with new agents that have prolonged survival relative to chemotherapy. 18 Such agents include tyrosine kinase BRAF-inhibitors (vemurafenib, dabrafenib), anti-MEK inhibitors (trametinib, cobimetinib), and monoclonal antibody anticheckpoint inhibitors to cytotoxic lymphocyte antigen-4 (CTLA-4) (ipilimumab) and to programmed death-1 (PD1) (nivolumab, pembrolizumab). The best results to date have been achieved with combinations of anti-BRAF/anti-MEK for patients with BRAF mutations, 19 and anti-CTLA4/anti-PD1 for all patients. 20 However, these therapies do not benefit all patients and are associated with significant toxicities. In a pooled analysis of 1,861 patients, anti-CTLA-4 was associated with a 20% 5-year survival rate, 21 but reliable 5-year survival data are yet to be reported for anti-PD1 therapy or the combination of anti-CTLA4/anti-PD1. However, based on early survival data, it is likely that even the combination will be associated with 5-year survival in only a minority of patients. 20
The presumed mechanism of action of eltrapuldencel-T is the induction of new immune responses or enhancement of weak immune responses to TAA. This should be complementary to the immune effects resulting from anti-CTLA-4 and anti-PD1 or anti-PDL1 antibodies because those agents rely on “taking the brakes off” previously existing immune responses to highly antigenic TAA that have been suppressed. 22 Eltrapuldencel-T appears to be associated with an overall survival benefit, but not with short-term objective responses or enhanced progression-free survival. 6,7 This discordance between apparent tumor progression and overall survival has been observed with other immunotherapies. 23 One patient who received eltrapuldencel-T in the randomized trial eventually obtained a complete remission of refractory, measurable, progressing disease, but that effect could not be documented until 15 months after initiating therapy. 24 Survival benefit with eltrapuldencel-T is evident both in patients who have no evidence of disease at the time vaccine is initiated and in those who have active disease. 25
Footnotes
Acknowledgment
The clinical trials in which these patients were treated were supported by the Hoag Hospital Foundation.
Disclosure Statement
The author was formerly an employee of Caladrius Biosciences, Inc., and owns stock in the company. Caladrius now owns the rights to eltrapuldencel-T (CLBS20).