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The Long and Winding Road to Effective Immunotherapy in Patients with Adrenocortical Carcinoma
Salvatore Grisanti, Deborah Cosentini, Marta Laganà, Alberto Dalla Volta, Carlotta Palumbo, Guido Alberto Massimo Tiberio, Sandra Sigala & Alfredo Berruti
To cite this article: Salvatore Grisanti, Deborah Cosentini, Marta Laganà, Alberto Dalla Volta, Carlotta Palumbo, Guido Alberto Massimo Tiberio, Sandra Sigala & Alfredo Berruti (2020) The Long and Winding Road to Effective Immunotherapy in Patients with Adrenocortical Carcinoma, Future Oncology, 16:36, 3017-3020, DOI: 10.2217/fon-2020-0686
To link to this article: https://doi.org/10.2217/fon-2020-0686
Published online: 28 Aug 2020.
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Future ONCOLOGY
The long and winding road to effective immunotherapy in patients with adrenocortical carcinoma
Salvatore Grisanti*,1D, Deborah Cosentini1, Marta Lagana1, Alberto Dalla Volta1D, Carlotta Palumbo2D, Guido Alberto Massimo Tiberio3D, Sandra Sigala4 D & Alfredo Berruti1 İD
1 Medical Oncology Unit, Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, University of Brescia, ASST Spedali Civili of Brescia, Brescia, 25123, Italy
2 Urology Unit, Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, University of Brescia, ASST Spedali Civili of Brescia, Brescia, 25123, Italy
3 Surgical Unit, Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, University of Brescia, ASST Spedali Civili of Brescia, Brescia, 25123, Italy
4Department of Molecular & Translational Medicine, Section of Pharmacology, University of Brescia, Brescia, 25123, Italy *Author for correspondence: grisanti.salvatore@gmail.com
“Cancer immunotherapy is still in its infancy, and these trials in ACC should be tagged as early pioneering attempts. However, they hold the undisputable merit to represent the first evidence of a clinical activity of ICI therapy in ACC.”
First draft submitted: 5 July 2020; Accepted for publication: 4 August 2020; Published online: 28 August 2020
Keywords: Adrenocortical carcinoma . hypercortisolism . immune checkpoints inhibitors . immunogenicity . im- munotherapy . PD-L1 . progression-free survival . tumor infiltrating lymphocytes
Adrenocortical carcinoma (ACC) can overall be considered an orphan disease with a known poor prognosis due to medium-low response rates to conventional chemotherapy and emergence of chemoresistance properties [1]. Furthermore, the traditional approach used in molecular target therapy, to inhibit the one, most overexpressed target, has proven to be unsuccessful in this disease [2]. In this scenario, it is of utmost importance to find new treatment strategies.
On the wave of enthusiasm for the success rate of immunotherapy with immune checkpoint inhibitors (ICIs) in many solid tumors and hematological neoplasms, in the past 2 years several groups investigated the role of ICI therapy in advanced ACC.
The scientific rationale for these studies mainly relies on four points of background information. First, ACC has an intermediate tumor mutation burden and in particular, a high frequency of inactivating somatic or germline mutations of genes of the DNA mismatch repair (MMR) system that causes enhanced instability of microsatellite loci (MSI-H) [3]. Considering that MMR-deficient (MMR-D) cancers are associated with neoantigens generation, they are usually considered more sensitive to ICI therapy [4]. Thus, MMR-D/MSI-H status in ACC could identify patients more responsive to immunotherapy. Second, autoimmune adrenalitis has seldom been described in patients receiving ICI therapy for a variety of solid tumors indicating the existence of a pool of autoreactive cytotoxic T cells infiltrating the adrenal gland [5]. Third, the ligand for immune checkpoint PD-1 protein (namely PD-L1) is expressed on adrenocortical tumor tissue albeit at low levels [6]. Fourth, few if any therapeutic alternatives are available for metastatic ACC patients failing one to two lines of systemic treatment, and immunotherapy could represent a potential new treatment.
With the preceding premises, four clinical trials with ICIs have been completed and three case series have been published with a current cumulative evidence on 123 treated patients. A recent review by Brabo et al. has recently summarized these data [7]. These trials differed in terms of ICI agent used (avelumab, pembrolizumab and nivolumab), patients characteristics (hormonal hypersecretion, number of previous lines of treatment, concomi-
Future Medicine
tant mitotane) and tumor biological features (MSI status, PD-L1 tissue levels, tumor-infiltrating lymphocyte [TIL] scores).
In 2018, Le Tourneau et al. published results of a Phase Ib trial of avelumab, an anti-PD1 antibody in metastatic ACC [8]. 50 pretreated (median two lines) ACC patients received avelumab monotherapy, and 50% of them maintained previous mitotane therapy. A PD-L1 score ≥1% on tumor tissue was detected in 30% of patients. No data on microsatellite instability status (MSI-H) or TILs were reported nor about hormonal secretion of ACC. Three (6%) and 21 (42%) patients obtained a partial response (PR) or stable disease (SD) with an overall response rate (ORR) of 6%. Median progression-free survival (PFS) and overall survival (OS) were 2.6 and 10.6 months, respectively.
In 2019, two trials reported results of treatment with the anti-PD-1 pembrolizumab in 52 ACC patients. In one trial, Habra et al. treated 14 ACC patients [9]. All patients were pretreated (two lines), 50% of them had hypercortisolism and none received concomitant mitotane. No patient showed MSI-H status and PD-L1 score >1%. However, 93% of patients showed a TIL infiltration score > 1. Two (14%) and seven (50%) patients obtained a PR or SD with an ORR of 14%. Median PFS and OS were not reported, but the 7-month PFS (nine cycles) was 36%. Noteworthy, patients with versus without hypercortisolism had a median increase of tumor lesions from a baseline of 22.6 vs 13%, respectively.
In the other pembrolizumab trial, Raj et al. treated 39 patients who had received one previous line of therapy [10]. Hormone hypersecretion status was not reported, and concomitant mitotane was not allowed. Six (16%) cases were MSI-H, 7/34 (21%) had a PD-L1 score >1% and all (100%) had a TIL score >1. Nine (23%) and seven (18%) patients had PR or SD with an ORR of 23%. Two patients had radiological pseudoprogression that preceded prolonged clinical response. Median PFS and OS were 2.1 and approximately 25 months (not reached), respectively.
Finally, Carneiro et al. treated ten ACC patients with the anti-PD-1 nivolumab in a single-arm Phase II trial with concomitant mitotane [11]. Patients had received one previous line of therapy, and 40% of them had hormone hypersecretion. MSI-H status was not detected and six (60%) and 10 (100%) patients had a PD-L1 score >1% and a TIL score >1, respectively. One (10%) and two (20%) patients had PR or SD with an ORR of 10%. Median PFS and OS were 1.8 and 21.2 months, respectively. Again, patients with hypercortisolism progressed early after two cycles of treatment.
There are at least four observations that can be derived from critical review of these trials:
· Although no complete responses have been observed, PRs were documented in 15/115 patients giving an approximated ORR of 13%. Stable disease was reported in 37/115 (32%) patients. Thus, the overall clinical benefit ratio (PR + SD) was 45% at approximately 4 months. Both time to achievement of response and duration of response were extremely variable;
· Median PFS (where reported) was between 1.8 and 2.6 months and median OS was between 10.6 and 24.9 months;
· Due to low numbers of patients and different reporting systems, apparently no clear correlations were observed between MSI status, PD-L1 expression, TIL score and clinical response;
· No correlation was observed between the number of previous lines of treatment and response. Concomitant mitotane seemed to have no impact on outcome. However, cortisol hypersecretion seemed to correlate with a worse response to treatment.
Cancer immunotherapy is still in its infancy, and these trials in ACC should be tagged as early pioneering attempts. However, they hold the undisputable merit to represent the first evidence of a clinical activity of ICI therapy in ACC.
Is this activity clinical meaningful? In his provocative editorial on the Javelin trial results, Fojo clearly states that a 1.8-2.6-month PFS obtained with immunotherapy is indeed not meaningful [12]. Unfortunately, the currently available therapeutic armamentarium for second or third line in advanced ACC does not perform much better. Both combination chemotherapy with gemcitabine and capecitabine or temozolomide monotherapy provide a clinical benefit rate in <50% of patients, and median PFS is <4 months [13,14].
Although not clinically meaningful for the majority of advanced ACC patients, a few of them did perform better and longer on ICI. This observation raises the critical issue of selecting the right ACC patient for ICI therapy.
The immunological landscape of ACC is poorly understood, and to date conventional tumor-derived markers such as PD-1/PD-L1 expression, tumor mutation burden, MRD-D/MSI-H and TILs appear to be less informative in this disease. On the clinical side, cortisol hypersecretion could represent a potential negative predictive factor. Conversely, the occurrence of pseudoprogression during ICI therapy when associated with clinical improvement could predict a favorable outcome and highlights the importance of introducing dynamic radiological response criteria [15].
However, this is not only a problem of patient selection. Drivers of potential immunoresistance are intrinsic properties in ACC including the immunosuppressive effect of glucocorticoids, exclusion of T-cell subsets induced by constitutive activation of Wnt/B-catenin signaling pathway and p53-mediated reduced chemokine/NK-cell in- terplay [16,17]. Results of The Cancer Genome Atlas (TCGA) showed that ACC is characterized by a signature of T-cell suppression with an inverse correlation between transcriptional programs of steroidogenic machinery and immune cell infiltration [18]. Despite that high numbers of TILs in ACC tissue have been described by several groups [10-12,19], they are probably pre-existing cytotoxic T cells from exhausted clones unable to expand after ICI therapy. Thus, ACC primary immunoresistance is the result of equally deficient regulatory and effector arms of innate and adaptive immunity.
A recent work by Wang et al. focused on immunotherapy response as a function of tumor immunogenicity (TIG), which in turn is the result of tumor antigenicity (e.g., neoantigen load) and antigen presentation capacity [20]. The striking observation was that neoplasms with a low TIG score had low response rates to immunotherapy despite huge antigenicity. In a TIG-based reclassification of the 33 TCGA human cancers, ACC segregates in a group of tumors with known poor response to immunotherapy, including low-grade glioma, uveal melanoma and testicular germ cell tumor. All of these tumors come from anatomical sites that are considered ‘immune-privileged’.
In the light of these insights, the low response rates observed in early clinical trials of ICI therapy in ACC are not surprising. In the future, better outcomes could be achieved by selecting patients with low steroidogenic properties (TCGA cluster of clusters 1) or combining ICI and therapies for ACC-associated hypercortisolism such as metyrapone or abiraterone. Although the number of previous lines of treatment did not show an impact on ICI outcome, heavily pretreated patients have lower chances of responding to any therapy. Thus, the ideal clinical arena for ICI therapy in ACC could be in the first or second line of treatment, and the idea of a randomized Phase III trial of immunotherapy versus standard EDP chemotherapy could be explored. Finally, the presumed immune privilege of ACC will require new pharmacological strategies to enhance antigen presentation capacity and immunogenicity of this rare cancer.
The road toward effective immunotherapy in ACC is still long and winding.
Author contributions
S Grisanti was responsible for conceptualization, data interpretation and writing. D Cosentini, M Laganà AD Volta and C Palumbo handled data acquisition. GAM Tiberio and S Sigala provided data interpretation and critical review. A Berruti was re- sponsible for conceptualization, data interpretation and critical review.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or finan- cial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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