Saturday, December 22, 2018

Reports on Intralesionals for melanoma - T-VEC, SD-101, and Dendritic cells

I have a few posts regarding melanoma that got put a bit on the back burner given the chaos that descended upon my world in August.  In the spirit of waste not, want not - thought I'd finish up the year with the last things that looked interesting in melanoma world ~

I still believe that intralesional therapies, especially when combined with a systemic therapy like Opdivo or Keytruda, are going to prove to be of great benefit to many melanoma patients!!!  Here are a zillion links to prior posts:  Intralesional/intratumoral therapy for Melanoma

Here are prior reports on T-VEC:  T-VEC (Talimogene Laherparepvec) for Melanoma  Now, there's this:

Talimogene Laherparepvec (TVEC) for the Treatment of Advanced Melanoma: A Single-Institution Experience.  Perez, Mirua, Naqvi, et al.  Ann Surg Oncol. 2018 Oct 8.   

Talimogene laherparepvec (TVEC) is an oncolytic herpes virus used as intralesional therapy for patients with unresectable stage IIIB through IV melanoma. We reviewed the standard of care treatment of TVEC at a single institution.  All patients treated with TVEC for advanced melanoma were retrospectively evaluated from 2015 to 2018. Patient demographics, clinicopathologic characteristics, treatment response, and toxicity were reviewed.  Twenty-seven patients underwent therapy with TVEC. Median age was 75 years, and 63% of patients were female. Seventeen (63.0%) patients underwent injections on the lower extremity, four (14.8%) on the upper extremity, four (14.8%) on the head and neck, and two (7.4%) on the trunk. Median number of injections was five. Median follow-up was 8.6 months. Of the 27 patients, 23 patients met the criteria for response analysis with at least 8 weeks follow-up. Ten (43.5%) patients experienced a complete response (CR), three (13.1%) experienced a partial response (PR), and five (21.7%) had stable disease (SD) for an overall response rate of 56.5% (CR + PR) and a disease control rate of 78.3% (CR + PR + SD). Adverse events were mostly limited to mild constitutional symptoms within 48 h of injection. Two patients developed cellulitis treated with oral antibiotics, and one patient underwent excision of a lesion for ulceration and bleeding during therapy. TVEC is an effective and well-tolerated intralesional therapy for patients with unresectable stage IIIB through IV melanoma. A CR was achieved in almost half of patients treated. Disease control is seen in the vast majority.  

SD-101 is another intralesional that is proving to have good results.  Here are prior reports:  SD - 101 in melanoma  Now, this summer, there was this:

SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study.  Ribas, Medina, Kummar, et al. Cancer Discov. 2018 Aug 28.

PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate "flu-like" symptoms. Among the 9 patients naïve to anti-PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti-PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8+ T cells, natural killer cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions.

These early data demonstrate that the combination of pembrolizumab with intratumoral SD-101 is well tolerated and can induce immune activation at the tumor site. Combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially increase clinical efficacy with minimal additional toxicity relative to PD-1 blockade alone.

Dendritic cells have been examined in many ways in melanoma care:  Dendritic cells in Melanoma  This study looks at them as an intralesional treatment combined with anti-PD-1 and radiation - in MICE:

Administration of dendritic cells and anti-PD-1 antibody converts X-ray irradiated tumors into effective in situ vaccines. Wang, Zenkoh, Gerelchulum, et al. Int J Radiat Oncol Biol Phys. 2018 Nov 17.  
Danger signals and release of tumor-specific antigens after exposure to ionizing radiation can convert an irradiated tumor into an in situ vaccine. However, radiation alone is not sufficient to induce an effective systemic immune response. In this study, we investigated whether a combination of X-ray irradiation with bone marrow-derived dendritic cell (BM-DC) and anti-PD-1 antibody (αPD1-ab) administration can enhance both local tumor control and the systemic abscopal effect in murine subcutaneous tumor models.
B16/BL6 melanoma and Lewis lung carcinoma (LLC) cells were examined of radiosensitivity and expression of H-2kb and PD-L1 before and after irradiation. The tumor cells were implanted subcutaneously in the left thigh of C57BL/6 mice as primary tumors. BM-DCs were induced from mouse bone marrow cells using GM-CSF and IL-4. The primary tumors were treated with 8 Gy of X-ray, followed by simultaneous intratumoral injection of BM-DCs and intraperitoneal injection of αPD1-ab. To examine the abscopal effect, the same tumor cells were also inoculated in the right thighs as metastatic tumors 4 days after the primary tumor inoculation, and only the primary tumors were treated with the same protocols. In vivo analyses of tumor growth and survival rates as well as in vitro analyses of splenic T-cell proliferation and interferon-γ (INF-γ) release were performed.  
The triple combination treatment of X-ray irradiation with BM-DC and αPD1-ab administration inhibited primary tumor growth and significantly extended the survival time in association with significant increase of T-cell proliferation and INF-γ release. In addition, this triple combination treatment significantly inhibited the growth of metastatic tumors.  The results indicated that BM-DC and αPD1-ab administration led to the conversion of irradiated tumors into effective in situ vaccines. This combination therapy can be a promising approach to develop a novel individualized therapy for patients with solid cancers.
Hang tough ratties!!! - c

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