Enhanced T-lymphocyte infiltration in a desmoid tumor of the thoracic wall in a young woman treated with intratumoral injections of the oncolytic peptide LTX-315: a case report

Desmoid tumors (DTs) or aggressive fibromatoses are rare, with a yearly incidence of 2–5 per 1 million population. Not apt to metastasize, they represent locally infiltrating soft tissue tumors that may occur anywhere in the body [1]. A seemingly multifactorial pathogenesis, including physical trauma, endocrine factors, and genetic aspects, induces a proliferation of fibroblasts, resulting in extremely hard, fibrotic lesions [2], approximately 90% of which comprise a somatic mutation of β-catenin (CTNNB1) [3]. The peak incidence is in the second to fourth decades of life, and a preponderance of the patients are female; otherwise, the sex incidence is equal in pediatric and older patients. The clinical development varies greatly from incidental findings of indolent course to progressive and mutilating disease imposing pain, major functional deficits, and even death in the case of intra-abdominal location. Symptomatic lesions call for action; however, treatment is challenging and often requires a trial-and-error approach [4‐6]. Owing to the confined nature of the disease, it seems rational to favor local treatment. Surgery often necessitates extensive resections and is associated with a high risk of local recurrence; hence, surgical excision is no longer considered a mainstay strategy [4, 5]. Radiotherapy entails a risk of severe late morbidity and secondary cancer. Recommended medications range from nonsteroidal anti-inflammatory drugs (NSAIDs) and endocrine treatment to kinase inhibitors and toxic chemotherapy [7‐11]. Immune therapy with recombinant interferon-α (IFN-α) or a human leukocyte derived mixture of naturally occurring IFN-α subtypes (Multiferon®) has been described as effective in selected cases [12, 13].

Relative contraindications to frequently used treatment options in a case of a young woman with a retromammary DT motivated the investigation of intratumoral injection of an oncolytic peptide within an ongoing phase I study in solid tumors. Long-term clinical benefit was achieved.

A young Caucasian woman (aged 29 years) was diagnosed in January 2013 with a DT (5 cm in longest diameter) infiltrating deeply into the left thoracic wall and involving multiple layers of soft tissue. Her only symptom was a palpable lesion; she had no pain. Surgery aiming for a wide safety margin would have required a massive resection and was considered contraindicated. During surveillance, the lesion gradually enlarged to approximately 8 cm, accompanied by increasing aching and tenderness. In addition, the patient experienced attacks of intense neuropathic pain causing frequent nocturnal awakenings, as well as restricted function of her left arm. Progressing tumor and debilitating symptoms compelled medical treatment. NSAIDs partially reduced pain but not tumor growth. Endocrine therapy with tamoxifen was discarded because the patient wanted a second child, and teratogenic effects have been reported and may persist as a risk many months after cessation of tamoxifen [14]. Instead, on the basis of Scandinavian experience, the patient received human IFN-α (Multiferon®) at a dose of 3 million IU daily administered subcutaneously in the period from May through August 2014 [12, 13]. Radiological evaluation demonstrated reduced growth kinetics and disease stabilization. However, the patient developed pneumonitis, and Multiferon® had to be stopped prematurely. Her pain did not diminish, but it was partially alleviated by ibumetin and later celecoxib in combination with paracetamol. Despite receiving pain relievers, she woke up approximately ten times every night and developed symptoms of sleep deprivation. Her young age and the retromammary localization of the tumor informed her reluctance to undergo radiotherapy, owing to a long-term risk of secondary breast cancer. Tyrosine kinase inhibitors have demonstrated promising progression-free survival, but only rarely has a partial regression pertinent to mitigating symptoms been achieved. Moreover, stable disease was already achieved with Multiferon®. Because the patient responded to immunotherapy with IFNs, we postulated that her tumor also might respond to intratumoral immunotherapy. She was therefore recruited to undergo local injection of an oncolytic peptide (LTX-315; Lytix Biopharma, Oslo, Norway) in an ongoing phase I study of solid tumors (ClinicalTrials.gov, NCT01986426) [15, 16].

DTs are classified as intermediate malignant lesions because of their infiltrative behavior [1]. Surveillance is recommended in asymptomatic cases because surgery entails a high risk of local recurrence correlating with the quality of the surgical margin [20]. Treatment is challenging in cases of rapid progression, and the severity of the disease directs the treatment decision process [4‐6]. When prompt response is crucial because of compromised function of vital organs, chemotherapy in oncological doses is typically the first choice [7]. Less dramatic development may motivate low-dose chemotherapy, IFN-α, or, more recently, tyrosine kinase inhibitors [8, 9]. Tamoxifen and NSAIDs (typically sulindac) are attempted in more indolent cases [10, 11].

Histopathological examination of DTs reveals uniform, spindle-shaped, small-nucleated cells within a collagen-rich stroma and variable prominent vessels or occasionally perivascular edema. Cellular atypia is absent [1]. Activating mutations of the CTNNB1 gene are detected in the majority of sporadic DTs counteracting the normal inhibitory effects of adenomatous polyposis coli (APC) protein on the β-catenin complex, a downstream effector of which the intricate function involves pleiotropy, interaction with transcription factors, cell growth, and homeostatic processes [3]. β-Catenin plays a key role in the Wnt-signaling cascade responsible for embryonal formation of tissue and organ development, as well as in cell regulation and regeneration in adults.

DTs most frequently arise in the abdominal wall in young/middle-aged women, in whom there is an association with pregnancy. Other locations are deep-seated, poorly circumscribed fibromatosis of the trunk wall, girdles, and head and neck area. Individuals with familial adenomatous polyposis (FAP) harbor an increased susceptibility to develop mesenteric/intra-abdominal DTs because germline inactivation of the APC tumor suppressor gene found in patients with FAP interrupts APC/β-catenin binding, resulting in inhibition of the Wnt pathway [21].

In young females, endocrine treatment with tamoxifen is considered first choice by many [22]. When we informed our patient about potential teratogenic side effects, she rejected this option. Anti-inflammatory drugs are frequently administered, but with limited success in most patients, as in our patient. Chemotherapy (acute and late toxicity concerns) and radiation (time-dependent risk of developing secondary cancer) were considered last-resort alternatives. Because of the relatively aggressive growth kinetics, we suggested human IFN-α, referring to a retrospective Norwegian study (see details below) [13]. Although side effects of IFNs may be distressing, they typically attenuate within a few weeks after commencing treatment and dissipate within 2 weeks after termination.

It is speculated whether DTs are offshoots of an out-of-control repair process following tissue injury; hence, an immunological mechanism may well play a part in the pathophysiological process. This is supported by clinical effects of NSAIDs and IFN [12, 23, 24]. In the period 2008–2013, Poulsen et al. conducted a study at the Norwegian Radium Hospital using Multiferon®, a purified, multi-subtype IFN-α product containing α1, α2, α8, α10, and α21, in patients with locally advanced DTs. Daily doses of 3 million International Units (IU) × 6 days/week were injected subcutaneously. The outcomes in 18 treated patients were partial response in 5, stable disease in 11, and progressive disease in 1, and 1 was not evaluated [13]. Treatment time ranged from 8 to 38 months and resulted in symptom relief in the majority of patients.

Our patient received Multiferon® in similar daily doses for 4 months, resulting in disease stabilization. Side effects were flulike symptoms and malaise. With time, however, she developed a dry cough and dyspnea. Computed tomographic findings correlated with pneumonitis, a relatively rare but known severe side effect of IFN, which had to be stopped.

Suggested immunological activity in the lesion motivated further immunotherapy with local application to reduce the risk of systemic side effects. Weighing the risks of experimental treatment against chemotherapy or radiotherapy harmfulness, building on a favorable toxicity profile of LTX-315 in animal models and early human testing, the patient was thoroughly informed about and consented to participation in the phase I study of transdermal injection of the oncolytic peptide LTX-315 in solid tumors. Intratumoral LTX-315 resulted in reversal of tumor growth kinetics in parallel with gradual symptom relief and a slight decline in tumor diameter. Ongoing stable disease represents a successful long-term outcome.

Safety aspects in 61 patients receiving LTX-315 at doses of 2–7 mg/injection displayed 11 cases of grades 3–4 allergic reactions, the most serious (anaphylaxis) of which occurred after > 10 weeks of treatment, indicating development of specific antibodies over time with repeated drug exposure. This was taken into account in the amended protocol, restricting treatment time to a total of 3 weeks, compensated with multiple concurrent injections in one or more lesions. Commonly recorded adverse events were mild and transient hypotension, flushing, skin rash, and pruritus in approximately 50%. All allergy-like reactions typically subsided within approximately 30 minutes, with no late sequelae.

In summary, in cases of DTs interfering with daily function, action is warranted in order to control the disease. The therapeutic outcomes achieved with different drugs are unpredictable, although in general, the more toxic the therapy chosen from the armamentarium, the greater the anticipated effectiveness. In our patient, we opted for an experimental drug in a third-line setting (following NSAIDs and IFN-α). Occurrence of a severe allergic reaction led to termination of the study drug. Altogether, a 16-week period of LTX-315 therapy was followed by a gradual change in pain. Despite increased local tenderness during the treatment period, a long-term improvement of distress complemented by a slow reduction of tumor size suggested clinical benefit. A polyclonal expansion of PBMC was accompanied by an almost 17-fold increase in CD3⁺ T lymphocytes infiltrating the tumor tissue, transforming the immune gene expression from cold to hot and confirming activity of the drug. A slowly symptomatic recovery over several months in respect to improved sleep and physical functioning due to alleviated pain supports this conclusion. Further studies using local immunotherapy with LTX-315 in patients with DTs seem justified.