Robert H. I. Andtbacka

Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy

Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic Txa0cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurred. Confirmed objective response rate was 62%, with a complete response rate of 33% per immune-related response criteria. Patients who responded to combination therapy had increased CD8+ Txa0cells, elevated PD-L1 protein expression, as well as IFN-γ gene expression on several cell subsets in tumors after talimogene laherparepvec treatment. Response toxa0combination therapy did not appear to be associated with baseline CD8+ Txa0cell infiltration or baseline IFN-γ signature. These findings suggest that oncolytic virotherapy may improve the efficacy of anti-PD-1 therapy by changing the tumor microenvironment. VIDEO ABSTRACT.

Severe Liver and Skin Toxicity After Radiation and Vemurafenib in Metastatic Melanoma

Case Report A 15-year-old girl underwent wide local excision and sentinel lymphadenectomy of a thin, nonulcerated melanoma. One of 16 lymph nodes contained a focus of microscopic metastasis. Staging imaging showed no other disease. After the first of 12 planned months of adjuvant interferon alfa, the medication was discontinued early because of significant fatigue. New lung nodules were detected on surveillance computed tomography (CT) imaging 3 years after diagnosis, and a biopsy confirmed melanoma. Magnetic resonance imaging (MRI) of the brain also showed a new metastasis to the right parietal bone. The patient was started on high-dose interleukin-2. Follow-up MRI showed local progression of the skull lesion, so stereotactic radiation (RT) involving 25 Gy over five treatments was given after her second interleukin-2 cycle. Adverse effects of RT included alopecia and faint erythema in the radiated area. The patient developed back pain, and surveillance CT scans 2 weeks later showed new bone metastases in the axial skeleton, liver and spleen metastases, and progression in her lungs. BRAF mutation testing of a subcutaneous metastasis that was excised from the back showed a V600E mutation. The patient was enrolled onto a phase II study investigating vemurafenib in metastatic melanoma that was approved by the institutional review board of the University of California, Los Angeles. Her initial vemurafenib dose was 960 mg twice per day. Within 14 days, her performance status improved, with a substantial decrease in her spinal pain. No photosensitivity was observed. After 1 month, CT scans showed progression of bone metastases, but the disease in her liver, lungs, and spleen was either stable or decreased. After withholding vemurafenib for 4 days, 20 Gy of RT was administered over five fractions to the painful bone metastases. A posterior-anterior (PA) beam was used for T1 to T7 and T10 to L1, and her bilateral acetabula were treated with an AP/PA arrangement. Vemurafenib was restarted 2 days after the completion of RT. Two weeks after RT, the patient developed a tender, raised rash with well-delineated borders that matched her RT portals (Fig 1, portals are indicated in yellow; Fig 2, portals are indicated in cyan). Dry desquamation and then resolution of the skin changes occurred within 4 weeks. Imaging performed 3 weeks after RT showed overall stability of non-CNS disease, but 12 new brain metastases were detected. Although whole-brain therapy would be standard treatment in this scenario, because of significant concerns about skin toxicity, stereotactic radiosurgery (SRS) to each brain metastasis was recommended. Two weeks later the patient developed lower extremity weakness, and a lumbar spine MRI showed cauda equina compression at L4. She received 8 Gy of RT to L2 to L5 using a PA field, but vemurafenib was only withheld for 2 days because of the emergent nature of the treatment. Three days later, 20-Gy SRS was performed on each of the brain metastases. Vemurafenib was restarted 4 days after SRS, beginning at 480 mg for 3 days before moving to a full dose. Approximately 1 week after RT, she developed only mild erythema that matched the L2 to L5 portal. CT scans performed 10 weeks after the completion of her second course of RT showed interval pulmonary progression, with mixed responses elsewhere. Of concern was the development of innumerable, tightly packed, hypodense lesions in the liver that matched her previous RT portal (Fig 3A, pretreatment scan, black arrows indicate examples of liver metastases outside the RT portal; Fig 3B, posttreatment scan with RT isodose overlay [100 cGy 1 Gy]). Days later the patient developed severe chest discomfort and was admitted for pain control. The following 3 days she developed worsening abdominal pain and an acute drop in hematocrit. Interval accumulation of a large subcapsular hepatic hematoma and hemoperitoneum consistent with hepatic hemorrhage were detected on CT imaging (Fig 3C, white arrows). The patient died 2 days later. An autopsy showed an enlarged liver with multicystic change that was mostly limited to the central liver. Microscopically, these cysts were hemorrhagic and lined with melanoma cells (Fig 4A, 20 magnification of subcapsular cyst lined by melanoma. Organizing clot was seen emerging through ruptured cysts, explaining the sudden drop in hematocrit. Fig 4B, 40 magnification of multiple cysts lined by melanoma [arrow]; Fig 4C, 400 magnification). The intervening liver parenchyma showed severe zone III necrosis and scattered venous thrombi that were consistent with radiation-induced liver toxicity. However, outside of the radiation field, the liver also showed zone III necrosis, although it was less severe and without venous thrombi. This was suggestive of an additional source of liver damage subsequent to the initial insult, such as global ischemia. The late-occurring ischemic injury was likely the combined result of blood loss from a ruptured hematoma found at autopsy and multiorgan failure near the time of death.

Sentinel lymph node biopsy for melanoma in pregnant women

BackgroundThe incidence of melanoma is rising in young women of childbearing age. Melanoma diagnosed during pregnancy presents unique challenges. This study was conducted to determine the effect of sentinel lymph node biopsy (SLNB) for melanoma on maternal and fetal outcomes in pregnant women.MethodsA prospective melanoma database was retrospectively queried for women diagnosed with melanoma during or immediately before pregnancy as well as SLNB in pregnant women. The outcomes of SLNB for the mothers and fetuses were evaluated.ResultsFifteen pregnant women underwent wide local excision (WLE) and SLNB for melanoma from 1997 to 2012. The median gestational age was 20xa0weeks. More than half of the women noticed changes in the primary melanoma lesion during the pregnancy. The median Breslow thickness was 1.00xa0mm. Lymphatic mapping and SLNB were performed with some combination of radiocolloid or vital blue dye without adverse effects. Three patients had micrometastatic disease and underwent a completion lymphadenectomy. Sixteen children were born at a median gestational age of 39xa0weeks. The median 1- and 5-minute Apgar scores were 8 and 9, respectively. At a median follow-up of 54.4, months none of the patients had experienced recurrence, and all children were healthy and free of melanoma.ConclusionsIn this series of pregnant women with melanoma, SLNB was performed safely during pregnancy without adverse effects to the mothers and fetuses. We recommend that clinicians explain the risks and benefits of the SLNB procedure to pregnant women so an informed decision can be made about the procedure.

Final planned overall survival (OS) from OPTiM, a randomized Phase III trial of talimogene laherparepvec (T-VEC) versus GM-CSF for the treatment of unresected stage IIIB/C/IV melanoma (NCT00769704)

Meeting abstractsnnT-VEC is an oncolytic immunotherapy derived from herpes simplex virus type-1 designed to selectively replicate within tumors and to produce GM-CSF to enhance systemic antitumor immune responses. OPTiM, a randomized Phase III trial of T-VEC vs GM-CSF in patients with unresected

A Phase I/III, multicenter, open-label trial of talimogene laherparepvec (T-VEC) in combination with pembrolizumab for the treatment of unresected, stage IIIb-IV melanoma (MASTERKEY-265)

Meeting abstractsnnT-VEC is a herpes simplex virus-1-based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF, and stimulate antitumor immune responses. OPTiM, a Phase III trial of T-VEC vs GM-CSF in unresectable stage IIIB-IV melanoma, improved the primary endpoint

Combination of a novel oncolytic immunotherapeutic agent, CAVATAK (coxsackievirus A21) and immune-checkpoint blockade significantly reduces tumor growth and improves survival in an immune competent mouse melanoma model

Coxsackievirus A21 (CAVATAK™) is a bio-selected oncolytic immunotherapy virus. Following intratumoral (i.t) injection, CAVATAK selectively infects ICAM-1-expressing tumor cells, resulting in tumor cell lysis and a systemic immune-mediated anti-tumor response. A Phase II trial of i.t delivered CAVATAK (NCT01227551) in advanced melanoma patients has highlighted antitumor activity in both injected and distant non-injected lesions. Such responses have occurred at times when no circulating infectious CAVATAK was detected in patient serum and in an environment of high levels of anti-CAVATAK neutralizing antibodies. In further support of the generation of CAVATAK-mediated immune anti-tumor activity is the identification of a possible novel serum cytokine signature of elevated levels of IL-8 and IFN-γ in treated patients associated with tumor inflammation and systemic tumor response. Blockade of programmed death-1 (PD-1) in patients with metastatic melanoma has resulted in substantial tumor responses via a mechanism involving reversal of tumor-induced T cell suppression. We hypothesized that a combination of CAVATAK and PD-1 blockade may enhance anti-tumor responses, potentially leading to improved clinical activity. Preclinical studies in C57BL mice were conducted to assess the anti-tumor activity of CAVATAK and anti-mouse PD-1 (mPD-1) mAb in a B16-ICAM-1 melanoma immune competent mouse model. B16-ICAM-1 cells are murine melanoma B16 cells stably transfected to express human ICAM-1 allowing CAVATAK binding and cell infection. CAVATAK was administered i.t, while anti mPD-1 mAb was delivered intraperitoneally. Following treatment of the primary cutaneous B16-ICAM-1 tumor with 8 cycles of CAVATAK injections and 4 cycles of anti-PD-1mAb, mice were challenged with additional subcutaneous administration of B16 cells. Significant single agent anti-tumor activities against the primary B16-ICAM-1 tumor were observed in mice treated with either CAVATAK or anti-PD-1 mAb relative to saline controls. Combination of CAVATAK and anti-PD-1 mAb mediated significantly greater anti-tumor activity and offered greater survival benefit when compared to use of either agent alone. Of particular interest was the finding that a combination of CAVATAK and anti-PD-1 mAb was able to noticeably delay the onset of palpable tumor development following B16 cell challenge when compared to all other single agent treatment regimes. The significant anti-tumor activity mediated by the combination of CAVATAK and the checkpoint inhibitor antibody (anti-PD-1) observed in the presented murine melanoma model supports clinical evaluation of such an immunotherapeutic combination treatment regimen in patients with advanced melanoma.

Phase 1 results of a phase 1b/2, multicenter, open-label trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) vs ipi alone in previously untreated, unresected stage IIIB-IV melanoma

T-VEC is a herpes simplex virus type-1-derived oncolytic immunotherapy designed to produce GM-CSF and to selectively replicate in and lyse tumors to induce a systemic anti-tumor immune response. A phase 3 study of T-VEC in Stage IIIB-IV melanoma demonstrated a significant improvement in ≥ 6 mo durable response rate vs GM-CSF and a tolerable safety profile.

Phase II calm extension study: Coxsackievirus A21 delivered intratumorally to patients with advanced melanoma induces immune-cell infiltration in the tumor microenvironment

Meeting abstractsnnCAVATAK, an oncolytic immunotherapy, is a bio-selected oncolytic strain of Coxsackievirus A21 (CVA21). Following intratumoral (IT) injection, CVA21 preferentially infects ICAM-1 expressing tumor cells, resulting in viral replication, cell lysis, and a systemic anti-tumor immune

Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials

BackgroundTraditional response criteria may be insufficient to characterize full clinical benefits of anticancer immunotherapies. Consequently, endpoints such as durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12xa0months of treatment and lasting ≥6xa0months) have been employed. There has not, however, been validation that DRR correlates with other more traditional endpoints of clinical benefit such as overall survival.MethodsWe evaluated whether DRR was associated with clinically meaningful measures of benefit (eg, overall survival [OS], quality of life [QoL], or treatment-free interval [TFI]) in a phase 3 clinical trial of an oncolytic virus for melanoma treatment. To evaluate the association between DRR and OS and to mitigate lead time bias, landmark analyses were used. QoL was evaluated using the FACT-BRM questionnaire (comprising the FACT-BRM Physical, Social/Family, Emotional, and Functional well-being domains, the Additional Concerns, Physical and Mental treatment-specific subscales, and the Trial Outcome Index [TOI]). TFI was defined as time from the last study therapy dose to first subsequent therapy dose (including any systemic anticancer therapy for melanoma after study therapy discontinuation).ResultsFour hundred thirty-six patients were included in the intent-to-treat population. Achieving DR was associated with a statistically significant improvement in OS in a landmark analysis at 9xa0months (HRu2009=u20090.07; Pu2009=u20090.0003), 12xa0months (HRu2009=u20090.05, Pxa0<xa00.0001), and 18xa0months (HRu2009=u20090.11; Pu2009=u20090.0002) that persisted after adjusting for disease stage and line of therapy. Achieving a DR was associated with a longer median TFI (HRu2009=u20090.33; Pu2009=u20090.0007) and a higher TOI improvement rate (58.1% versus 30.0%; Pu2009=u20090.025).ConclusionsAchieving a DR was associated with clinical benefits such as improved OS and QoL and prolonged TFI, thus supporting the usefulness of DR as a meaningful immunotherapy clinical trial endpoint.Trial registrationClinicalTrials.gov identifier, NCT00769704 (https://clinicaltrials.gov/ct2/show/NCT00769704) October 7, 2008

1102PRESULTS OF THE EXTENSION TRIAL OF OPTIM, A MULTICENTER, RANDOMIZED PHASE 3 TRIAL OF TALIMOGENE LAHERPAREPVEC (T-VEC) VS GM-CSF FOR UNRESECTED STAGE IIIB-IV MELANOMA

ABSTRACT Aim: T-VEC is an HSV-1-derived oncolytic immunotherapy designed to selectively replicate in tumors and produce GM-CSF to enhance systemic antitumor immune responses. Compared to GM-CSF alone, T-VEC significantly improved durable response rate (DRR; partial response [PR] or complete response [CR] lasting continuously for ≥ 6 months [m]) from 2% to 16% (p Methods: Pts were eligible for the extension trial if: 1) they had received the maximum treatment (tx) cycles allowed on OPTiM and did not have disease progression (PD) associated with reduced performance status or 2) had a CR on OPTiM and then developed new lesions within 12 m. In the extension study, pts could continue their randomized tx: T-VEC (intralesional ≤ 4u2003mL × 108 pfu/mL q2w) or GM-CSF (sc 125 µg/m2 qd × 14 days q4w) until CR, additional 12 m of tx, PD or unacceptable toxicity. The primary endpoint was safety; efficacy was also evaluated. Results: 30 (27 T-VEC, 3 GM-CSF) of the 436 pts enrolled in OPTiM entered the extension trial. Including OPTiM tx, median duration of tx was 91 wks (range: 29-132) for T-VEC and 100 wks (54-120) for GM-CSF. Most common adverse events (AE) on each arm were chills and pyrexia. There were no grade 5 tx-related AEs. For T-VEC, 5 new CR occurred (best OPTiM response was 3 PR and 2 stable disease [SD]). Best overall response was maintained in 16 pts (1 CR, 6 PR, and 9 SD), 2 pts progressed from PR to SD; PD occurred in 4 pts. A new DR occurred in 1 T-VEC- treated pt. For GM-CSF, PR was maintained in 1 pt and 2 pts progressed from PR to SD. For both trials combined, CR, OR, and DR rates per investigator for T-VEC were 16.3%, 31.5%, and 19.3%, respectively, and 0.7%, 6.4%, and 1.4% for GM-CSF. Conclusions: Continued tx with T-VEC but not GM-CSF was associated with improved response rates, with 5 additional CR and one DR (ie. previously a response of Disclosure: R.H. Andtbacka: RHIA has participated in advisory boards for Amgen Inc.; T. Amatruda: TA has been a site principal investigator for trials funded by Amgen Inc. He has no financial conflicts of interest; J. Chesney: JC has participated in an advisory board for Amgen Inc.; F.A. Collichio: FC has been a consultant to Amgen and received research support from Bristol-Myers Squib, GSK, Morphotek and Amgen, all paid to her institution. (University of North Carolina). (per OPTIM MS disclosure); A. Li: AL is an employee of and shareholder in Amgen Inc.; K. Liu: KL is an employee of and shareholder in Amgen Inc.; M. Shilkrut: MS is an employee of and shareholder in Amgen Inc.; R. Coffin: RC has been a consultant to Amgen Inc. and is a shareholder in Amgen Inc.; H. Kaufman: HK has received honoraria from Amgen Inc. for participating in advisory boards and research funding to conduct clinical trials. All other authors have declared no conflicts of interest.