Liver transplant patient with in-transit squamous cell carcinoma treated with talimogene laherparepvec

cSCC: cutaneous squamous cell carcinoma IOs: immunotherapies NMSC: nonmelanoma skin cancer RT: radiation therapy SOTR: solid organ transplant recipients T-VEC: talimogene laherparepvec INTRODUCTION Nonmelanoma skin cancers (NMSCs), especially cutaneous squamous cell carcinomas (cSCCs), are extremely common in immunosuppressed patients. Most solid organ transplant recipients (SOTRs) are at markedly elevated risk for developing cutaneous malignancies due to the lifelong immunosuppression required to avoid allogenic graft reaction. While anti PD-1 based immunotherapy (IO) represents the standard of care for unresectable cSCC, the limited efficacy and concern for inducing graft rejection limits its use in SOTR. Recently, novel local therapies for the treatment of advanced or recurrent cutaneous malignancies have received significant attention. Talimogene laherparepvec (T-VEC) is the first intralesional oncolytic virus therapy with Food and Drug Administration (FDA) approval to treat advancedstage melanoma. Although T-VEC is not approved to treat NMSC and is contraindicated in immunosuppressed patients, there are some SOTRs for whom it is among the safest and most appropriate options. This report describes the treatment of SOTR patient with recurrent cSCC who underwent successful treatment with T-VEC as part of a multi-modality, limb-sparing approach to controlling the disease.


INTRODUCTION
Nonmelanoma skin cancers (NMSCs), especially cutaneous squamous cell carcinomas (cSCCs), are extremely common in immunosuppressed patients. 1ost solid organ transplant recipients (SOTRs) are at markedly elevated risk for developing cutaneous malignancies due to the lifelong immunosuppression required to avoid allogenic graft reaction.While anti PD-1 based immunotherapy (IO) represents the standard of care for unresectable cSCC, the limited efficacy and concern for inducing graft rejection limits its use in SOTR. 2 Recently, novel local therapies for the treatment of advanced or recurrent cutaneous malignancies have received significant attention.Talimogene laherparepvec (T-VEC) is the first intralesional oncolytic virus therapy with Food and Drug Administration (FDA) approval to treat advancedstage melanoma.Although T-VEC is not approved to treat NMSC and is contraindicated in immunosuppressed patients, there are some SOTRs for whom it is among the safest and most appropriate options. 3,4his report describes the treatment of SOTR patient with recurrent cSCC who underwent successful treatment with T-VEC as part of a multi-modality, limb-sparing approach to controlling the disease.

CASE REPORT
A 71-year-old man with a history of Evan's syndrome, orthotopic liver transplantation in 2016, and recurrent cSCC of the left forearm presented to Duke Cancer Institute for management of an additional recurrent cSCC.Four years prior to presentation, he underwent a whole, deceased-donor liver allotransplantation due to end stage liver disease secondary to autoimmune hepatitis and primary sclerosing cholangitis.Postoperative complications included biliary enteric anastomotic stricture requiring reoperation, as well as subsequent infections.The following year he had an acute rejection episode requiring pulsed IV steroids and an increased dosing of immunosuppressants.At presentation for his most recent recurrence of cSCC, his immunosuppression regimen consisted of prednisone 5 mg once daily, tacrolimus 2 mg once in the morning and 1 mg nightly, and mycophenolate 250 mg twice daily.Mycophenolate was later discontinued and replaced with sirolimus 2 mg daily due to his recurrent cSCC.
Two years post-transplantation, the patient noticed a suspicious lesion on his left arm and was diagnosed with moderately differentiated cSCC.Subsequently, Abbreviations used: cSCC: cutaneous squamous cell carcinoma IOs: immunotherapies NMSC: nonmelanoma skin cancer RT: radiation therapy SOTR: solid organ transplant recipients T-VEC: talimogene laherparepvec over a 2-year period, he underwent 4 Mohs micrographic surgeries on his left proximal forearm and elbow region, skin grafting, and from lack of disease control, underwent adjuvant external beam radiation therapy (RT).Two years after initial cSCC diagnosis, he developed recurrence as in transit metastasis on his left arm, with 3 punch biopsies of separate lesions showing metastatic, moderately to poorly differentiated cSCC involving the deep dermis with areas of ulceration and lymphovascular invasion.PET CT imaging showed hypermetabolic skin thickening about the left elbow and forearm with lesions ranging from 5 to 23 mm.Additional surgery was unfavorable given the pattern of disease recurrence.Treatment consideration was given to regional chemotherapy with isolated limb infusion, but given the risk of hepatotoxicity and limb-threatening toxicity, this option was less favorable.Systemic immunotherapy (IO) with an anti-PD-1 antibody was reserved as a last resort due to the risk of life-threatening organ rejection and limited efficacy in immunosuppressed patients. 5,6EGFR inhibitors were disfavored due to the risk of toxicity.Finally, intralesional treatment with the oncolytic viral agent, T-VEC, was discussed.There was concern for toxicity, particularly for a disseminated herpesvirus infection, but based on literature review and discussions, this risk was deemed as low.The patient was treated with T-VEC therapy in accordance with FDA prescribing, using an initial concentration of 10 6 pfu/ml followed by 10 8 pfu/ml for all subsequent treatments (Table I).T-VEC treatment consisted of 32 cycles every 2 wk over a 15-month period (Table I).After complete elimination of all lesions with T-VEC and 1 surgical excision, a new focus of hypermetabolic activity was visualized at the ulnar aspect of the forearm via PET imaging.Fine needle aspiration of the palpable subcutaneous nodule revealed a new in-transit lesion of cSCC.Notably, because this lesion progressed rapidly and did not show early signs of responsiveness to T-VEC, the treatment was terminated and definitive external beam RT was administered.Treatment consisted of 6 fractions of 600 cGy for a total dose of 3,600 cGy using en face electrons at 6 MeV.Following RT, the patient has continued surveillance with physical exam and cross-sectional imaging.Thirteen months post T-VEC discontinuation, imaging revealed no evidence of active disease.
He tolerated the treatment well overall.Of note, between T-VEC treatment 6 and 7, the patient was thrombocytopenic with counts ranging from 20,000 to 80,000.Attribution to T-VEC treatment was felt to be unlikely.He did not experience any bleeding complications during this time and was managed medically with eltrombopag.Platelet counts  returned to normal range within 2 months of initiating treatment, and no other side effects have been reported.Importantly, he experienced no clinically evident herpesvirus infection. 7

CONCLUSIONS
Intralesional oncolytic viral therapy has potential clinical utility for patients with recurrent cSCC following SOTR and may be used as a multimodal treatment strategy.This case demonstrates the use of T-VEC therapy for the treatment of cSCC in a patient with complex medical history including liver transplantation, graft rejection, and autoimmune disease.The patient underwent 32 intralesional T-VEC treatments which helped eradicate his in-transit cSCC (Figs 1 and 2).The disease ultimately progressed, revealing a new solitary nodule, which completely resolved with RT.He has remained without evidence of recurrent disease 9 months after completion of RT.This case highlights the safety and utility of T-VEC to treat recurrent in-transit cSCC in a SOTR.Ongoing clinical trials, including the ARTACUS trial (NCT04349436), a phase Ib/II study evaluating intralesional RP1, a next-generation herpesvirus-based oncolytic therapy, in SOTR with advanced cutaneous malignancies, could establish this as a standard treatment strategy in the future. 9Further investigation is warranted to elucidate the utility of T-VEC in treating cutaneous cSCC in SOTR.The images depict a significant healing of lesions with re-epithelialization. Image (D), illustrates the new subcutaneous nodule measuring 2.5 cm that became noticeable just as the last of the prior lesions had completely resolved.
7,8 T-VEC treatment was offered to and elected by the patient.Due to the proposed off-label use of T-VEC, approvals were obtained through Duke Health IRB and regulatory oversight processes, and an individual patient FDA IND application.The drug was provided by Amgen free of charge through an expanded access program.Once treatment was initiated, 2 adjacent lesions had coalesced to form a large, ulcerated lesion (Fig 1).

Fig 1 .
Fig 1. Left forearm notable for multiple in-transit lesions of various sizes.Images (A and B), were taken on T-VEC treatment 2 (day 21) and images (C and D), on treatment 16 (day 217).

Fig 2 .
Fig 2. Left forearm notable for multiple in-transit lesions of various sizes.Images (A and B), were taken on T-VEC treatment 24 (day 336) and images (C and D), on treatment 32 (day 455).The images depict a significant healing of lesions with re-epithelialization. Image (D), illustrates the new subcutaneous nodule measuring 2.5 cm that became noticeable just as the last of the prior lesions had completely resolved.

Table I .
Talimogene laherparepvec treatment for the patient's left forearm squamous cell carcinoma lesions that occurred every 2 weeks for a period of 15 months