Intralesional Injections Trigger Immune Responses in Melanoma

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Howard L. Kaufman, MD, FACS

Merrick I. Ross, MD

Igor Puzanov, MD

Amod Sarnaik, MD

Sanjiv S. Agarwala, MD

Adil Daud, MD

After PV-10 injection, we saw a significant increase in circulating T cells, including CD3-positive and cytotoxic CD8-positive cells. This suggests an immunologic-mediated antitumor response is engendered by PV-10.

—Amod Sarnaik, MD

The emerging approach to treating metastatic melanoma is a full-throttle effort to stimulate an immune response. One of the components of this strategy could be intralesional injections, according to studies presented at the 2014 ASCO Annual Meeting.

T-VEC Oncolytic Immunotherapy

Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1–derived investigational oncolytic immunotherapy. It is designed to induce local and systemic immune responses in several ways: by selectively replicating in cancer cells while producing granulocyte-macrophage colony-stimulating factor (GM-CSF) at the site of injection; by lysing cancer cells, resulting in the release of tumor-derived antigens; and by creating a microenvironment that promotes systemic immune responses against tumor-derived antigens.

The phase III OPTiM study of T-VEC in stage IIIB/IV melanoma included 295 patients treated with T-VEC and 141 treated with recombinant GM-CSF (Leukine) as the control arm. OPTiM met its primary endpoint of durable response, which was observed in 16.3% of the T-VEC arm and 2.1% of the control arm, creating an unadjusted odds ratio of 8.9 (P < .0001).1 The overall response rate was 26.4% and 5.7%, respectively.

At the ASCO Annual Meeting, Howard L. Kaufman, MD, FACS, Resident Member at Rutgers Cancer Institute of New Jersey, New Brunswick, presented the primary analysis of overall survival, a secondary endpoint.2 “An improvement that closely approached statistical significance was seen in the intent-to-treat population,” he said. Median survival was 23.3 months with T-VEC and 18.9 months with GM-CSF (hazard ratio [HR] = 0.79, P = .051), a 4.4-month improvement.

“In exploratory subset analyses, both durable response rate and overall survival effects appeared to be more pronounced among patients with stage IIIB/IV M1a disease and also among patients who were treated with T-VEC as first-line therapy,” he said.

Stage IIIB/C and IV M1a patients had a median overall survival of 41.1 months with T-VEC vs 21.5 months with GM-CSF (HR = .57, P < .001), whereas regardless of treatment, stage IV M1b/c patients had similar median overall survival times—13.4 months and 15.9 months, respectively. T-VEC given as first-line treatment yielded a median survival of 33.1 months, vs 17.0 for GM-CSF (HR = 0.50, P < .001), but had no effect in the second line, Dr. Kaufman reported.

Merrick I. Ross, MD, Professor in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center, Houston, described the patterns of durable response.3 “Approximately two-thirds of T-VEC responses have lasted at least 1 year,” he reported. “The majority of responders were still in response at the end of the evaluation period.”

The estimated probability of being in response at 12 months was 65% for patients who responded to T-VEC. Of 48 T-VEC–treated patients who achieved a durable response, 83% had responses ongoing at a median follow-up of 18.4 months.

As seen with other immunotherapies, disease progression prior to response did not negatively impact the frequency or duration of durable response, he said, suggesting that “T-VEC treatment through initial disease progression can be effective.”

T-VEC Plus Ipilimumab

The best way to use T-VEC, however, may be in combination with other immune therapies, melanoma experts have suggested. In a phase Ib trial that combined T-VEC with ipilimumab (Yervoy), high response rates were observed, including complete responses in one-third of patients, reported Igor Puzanov, MD, Associate Professor of Medicine at Vanderbilt University in Nashville.4

“Combining T-VEC, which promotes the release of tumor-derived antigens, with an immune checkpoint inhibitor that improves T-cell responses, could potentially enhance the efficacy compared to either therapy alone,” Dr. Puzanov said.

The study enrolled 19 previously untreated patients whose tumors were injected with up to 4 mL of T-VEC, dosed periodically until all injectable tumors disappeared or until progressive disease or intolerance. All responders received four doses of ipilimumab at 3 mg/kg every 3 weeks for 4 weeks, starting at week 6. Durable responses were observed in 10 of 18 (56%) evaluable patients, 33% being complete responses; the disease control rate was 72%.

“These data, although preliminary, suggest higher overall and complete response rates than with either agent alone,” Dr. Puzanov commented.

Total and activated CD8 T cells increased after treatment with T-VEC and increased further with T-VEC plus ipilimumab. Ongoing investigation with additional T-cell markers is planned.

“The two treatments may be activating complementary clones of T cells, broadening the potential repertoire of antigens targeted. The translational studies of individual T-cell receptors are underway,” Dr. Puzanov told The ASCO Post.

There were no unexpected toxicities from the combination. The phase II part of the study is currently enrolling (70 previously untreated patients per arm), with the primary endpoint of overall survival.

Intralesional PV-10

Other promising results were achieved with intralesional PV-10, which contains a proprietary injectable formulation of rose bengal disodium, a water-soluble xanthene dye used in a topical opthalmic diagnostic.

Sanjiv S. Agarwala, MD, Chief of Medical Oncology and Hematology at St. Luke’s Cancer Center, Bethlehem, Pennsylvania, presented a subgroup analysis of an international phase II study of 80 patients. In the current analysis of 54 evaluable patients with cutaneous lesions, 28 underwent intralesional PV-10 injections in target and bystander lesions, while 26 had no bystander treatment.5

The overall response rate was 71% for the all-lesion group, with 50% complete responses; of those with injections in only the target lesions, 54% responded, and 23% had complete responses.

In addition, Amod Sarnaik, MD, Assistant Member at H. Lee Moffitt Cancer Center, Tampa, reported interim results of a pilot study of 13 patients treated with intralesional PV-10 designed to investigate the local and immunologic effects of tumor ablation.6

“[Intralesional] PV-10 can induce regression of injected and uninjected metastatic melanoma, enhance tumor-specific reactivity in circulating T cells, and lead to responses in treatment-refractory tumors,” Dr. Sarnaik said.

In a comparison of lesions before and after treatment, intralesional PV-10 led to pathologic complete responses in both PV-10-injected and uninjected study lesions in four of eight evaluable patients, and all eight exhibited at least partial regression of the injected lesions. These outcomes were observed even in patients with metastatic disease refractory to previous ipilimumab, anti–PD-1 antibodies and/or vemurafenib (Zelboraf).

“After PV-10 injection, we saw a significant increase in circulating T cells, including CD3-positive and cytotoxic CD8-positive cells. This suggests an immunologic-mediated antitumor response is engendered by PV-10. We are hoping to undertake combination trials that combine PV-10 with promising systemic immunotherapies,” Dr. Sarnaik said.

Intratumoral Electroporation of Plasmid IL-12

Intratumoral delivery of interleukin (IL)-12 via electroporation (which saturates drug into the tumor) may avoid systemic toxicity while promoting systemic antitumor immunity. In a phase II study presented by Adil Daud, MD, Clinical Professor of Medicine and Director of Melanoma Clinical Research at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, treated and nontreated tumors regressed with this approach and natural killer cells were increased.7

The 29 patients received at least one treatment cycle, which consisted of injections on days 1, 5, and 8 for a maximum of four cycles at 12-week intervals. Responses, which were assessed by a modification of RECIST criteria, were observed in 32.2%, of which 10.7% were complete responses. Among 22 evaluable patients, 13 (59.1%) had regression of untreated distant lesions. ■

Disclosure: Dr. Kaufman and Dr. Puzanov are consultants/advisors for Amgen. Dr. Ross is a consultant/advisor for and has received research funding from Amgen, and has received honoraria from Paradigm Medical Communications. Dr. Agarwala and Dr. Sarnaik have received research funding from Provectus Pharmaceuticals. Dr. Daud is a consultant/advisor for and has received research funding from OncoSec. For full disclosures of all study authors, visit


1. Andtbacka RI, Collichio FA, Amatruda T, et al: OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of unresected stage IIIB/C and IV melanoma. ASCO Annual Meeting. Abstract LBA9008. Presented June 1, 2013.

2. Kaufman HL, Andtbacka RI, Collichio FA, et al: Primary overall survival from OPTiM, a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous granulocyte-macrophage colony-stimulating factor for the treatment of unresected stage IIIB/C and IV melanoma. ASCO Annual Meeting. Abstract 9008a. Presented June 2, 2014.

3. Ross MI, Andtbacka RI, Puzanov I, et al: Patterns of durable response with intralesional talimogene laherparepvec (T-VEC): Results from a phase III trial in patients with stage IIIb-IV melanoma. ASCO Annual Meeting. Abstract 9026. Presented June 2, 2014.

4. Puzanov I, Milhem MM, Andtbacka RI, et al: Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and iplimumab in previously untreated, unresected stage IIIB-IV melanoma. ASCO Annual Meeting. Abstract 9029. Presented June 2, 2014.

5. Agarwala SS, Thompson JF, Smithers BM, et al: Efficacy of intralesional rose Bengal in patients receiving injection of an existing melanoma in phase II study PV-10-MM-02. ASCO Annual Meeting. Abstract 9027. Presented June 2, 2014.

6. Sarnaik A, Crago G, Liu H, et al: Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma. ASCO Annual Meeting. Abstract 9028. Presented June 2, 2014.

7. Daud A, Algazi P, Ashworth MT, et al: Systemic antitumor effect and clinical response in a phase 2 trial of intratumoral electroporation of plasmid interleukin-12 in patients with advanced melanoma. ASCO Annual Meeting. Abstract 9025. Presented June 2, 2014.

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