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HeberFERON, formulation based on IFNs alpha2b and gamma for the treatment of non-melanoma skin cancer

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Background Surgery remains the procedure of election for the treatment of non-melanoma skin cancer (NMSC). However, after recurrence, or under surgical complex scenarios, other therapeutic modalities have to be indicated. Immune suppression is associated to NMSC; thus, immunotherapy is a rational approach to treat the high spread form of skin tumour. Aims We propose a summary of the most relevant clinical results with the combination of IFNs alpha2b and gamma in the treatment of non-melanoma skin cancer. Methods In several clinical trials (Open prospective trial; phase 2 double-blind randomized studies: InCarbacel-II and InCarbacel-III; retrospective study and ongoing phase IV trial, InCarbacel-IV) more than 200 patients with histological diagnostic of non-melanoma skin cancer were recruited to be treated with the combination of IFNs in Cuban health institutions at primary, secondary or tertiary care levels. All the studies were approved by institutional ethic committees and all the patients given their written informed consent. HeberFERON was administered, peri- or intralesionally, three times per week, during 3 weeks. Clinical and histological responses were evaluated by RECIST (1.0), three months after the end of treatment. Results HeberFERON promoted more rapid and higher number of CRs than separated IFNs (InCarbacel-II study). The openlabel prospective study showed 46.7 per cent CR in locally advanced BCC after application of HeberFERON. Patients with periocular BCC or SCSC received benefits from HeberFERON treatment (71.4 per cent OR). Overall, HeberFERON has been administered to patients with nonmelanoma skin cancer obtaining a 65 per cent of histological CR together with an excellent safety profile. Conclusion HeberFERON is a novel, non-surgical, effective and safe option to treat advanced, high risk or recurrent nonmelanoma skin cancer.
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HeberFERON, formulation based on IFNs alpha2b and gamma for the treatment
of non-melanoma skin cancer
Lorenzo Anasagasti-Angulo1, Yanelda Garcia-Vega2, Sonia Collazo3, Yanisel Jimenez-Barban4, Edgar
Tijerino-Arrieta1, Yoddali Ballester-Caballero5, Vladimir Sánchez-Linares6, Jorge Marin-Guerra6,
Katherine Batista7, Yaquelin Duncan-Roberts8, Carmen Valenzuela-Silva2, Angela Tuero-Iglesias8,
Leovaldo Álvarez-Falcon8, and Iraldo Bello-Rivero8
1. Department of Medical Oncology, National Institute of Oncology and Radiobiology, Havana, Cuba
2. Center of Molecular Immunology, Havana, Cuba
3. “Hermanos Ameijeiras” Hospital, Havana, Cuba
4. Ophthalmology Center, “Enrique Cabrera” Hospital, Havana, Cuba
5. “Amalia Simoni” Hospital, Camagüey, Cuba
6. Policlinics Centro and Cabaiguan, Sancti Spíritus, Cuba
7. Policlinic Mario Gutierres Ardaya, Holguín, Cuba
8. Department of Clinical Research, Center for Genetic Engineering and Biotechnology, Havana, Cuba
509
[AMJ 2017;10(6):509515]
BRIEF REPORT
Please cite this paper as: Anasagati-Angulo L, Garcia-Vega Y,
Collazo S, Jimenez-Barban Y, Tijerino-Arrieta E, Ballester-
Caballero Y, Sánchez-Linares V, Marin-Guerra J, Batista K,
Duncan-Roberts Y, Valenzuela-Silva C, Tuero-Iglesias A,
Álvarez-Falcon L, Bello-Rivero I. HeberFERON, formulation
based on IFNs alpha2b and gamma for the treatment of
non-melanoma skin cancer. AMJ 2017;10(6):509515.
https://doi.org/10.21767/AMJ.2017.3013
Corresponding Author:
Iraldo Bello Rivero
Center for Genetic Engineering and Biotechnology
Ave 31. Cubanacán, Havana. Cuba
Email: iraldo.bello@cigb.edu.cu
ABSTRACT
Background
Surgery remains the procedure of election for the treatment
of non-melanoma skin cancer (NMSC). However, after
recurrence, or under surgical complex scenarios, other
therapeutic modalities have to be indicated. Immune
suppression is associated to NMSC; thus, immunotherapy is
a rational approach to treat the high spread form of skin
tumour.
Aims
We propose a summary of the most relevant clinical results
with the combination of IFNs alpha2b and gamma in the
treatment of non-melanoma skin cancer.
Methods
In several clinical trials (Open prospective trial; phase 2
double-blind randomized studies: InCarbacel-II and
InCarbacel-III; retrospective study and ongoing phase IV
trial, InCarbacel-IV) more than 200 patients with histological
diagnostic of non-melanoma skin cancer were recruited to
be treated with the combination of IFNs in Cuban health
institutions at primary, secondary or tertiary care levels. All
the studies were approved by institutional ethic committees
and all the patients given their written informed consent.
HeberFERON was administered, peri- or intralesionally,
three times per week, during 3 weeks. Clinical and
histological responses were evaluated by RECIST (1.0), three
months after the end of treatment.
Results
HeberFERON promoted more rapid and higher number of
CRs than separated IFNs (InCarbacel-II study). The open-
label prospective study showed 46.7 per cent CR in locally
advanced BCC after application of HeberFERON. Patients
with periocular BCC or SCSC received benefits from
HeberFERON treatment (71.4 per cent OR). Overall,
HeberFERON has been administered to patients with non-
melanoma skin cancer obtaining a 65 per cent of
histological CR together with an excellent safety profile.
510
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Conclusion
HeberFERON is a novel, non-surgical, effective and safe
option to treat advanced, high risk or recurrent non-
melanoma skin cancer.
Key Words
Interferons, non-melanoma skin cancer, non-surgical
Implications for practice:
1. What is known about this subject?
Some patients with non-melanoma skin cancer are difficult
to treat effectively. Advanced, high risk or recurrent lesions,
produces high morbidity and in some cases death.
2. What new information is offered in this report?
HeberFERON has been successful as a new therapeutic
options for patients with difficult to treat NMSC.
3. What are the implications for research, policy, or
practice?
HeberFERON should be recommended for those patients
with advanced BCC combined or not with other therapies. It
is highly recommended to avoid surgical mutilations as
therapeutic indication.
Background
Non-melanoma skin cancer (NMSC) is the most common
form of skin cancer. The predominant cause of NMSC is
largely associated to exposure to ultraviolet (UV) radiation,1
likely because of immune suppression.2,3 Mutations in
tumour suppressor genes, angiogenesis, dysregulation of
the Hedgehog (Hh) signalling pathway and evasion of
immune system response contribute to developing and
perpetuation of NMSC.4,5 However, contrary to basal cell
carcinoma (BCC), scarce link to genetic variations have been
attributed to squamous cell skin carcinomas (SCSC) risk.6
Human papilloma viruses (HPV) infections could function as
co-factor with UV-radiation for skin cancer risk.7
Malignant BCC cells arise from hair follicles, grow slowly and
invade locally.8 Recurrence of BCC is approximately 12 per
cent with the most habitual therapies. Between 40 per
cent50 per cent of patients with a primary lesion will
develop at least one further BCC within 5 years.9 The rate of
recurrence is highly correlated with tumour size and facial
location. Approximately 90 per cent of recurrent BCC are
related to head and neck. Aggressive histological BCC
subtypes recurred more frequently.10 SCSC can growth from
sites with actinic keratosis, chronic wounds or scarring, in
the epithelial keratinocytes.11 With respect to BCC, SCSC has
a higher risk of recurrence (8 per cent15 per cent) and
metastasis (0.5 per cent16.0 per cent).12
One per cent10 per cent of BCCs is difficult to treat, or is
more aggressive, or produces multiple recurrences with
difficulty for further local surgery or radiotherapy, or
requires substantial surgical excision with sometimes
complex reconstruction. This characterizes the subset of
BCC, called locally advanced basal cell carcinoma (laBCC).13
Surgical excision remains the gold standard of treatment for
BCC. When used excision with 34 mm margins, the results
are excellent.14 However, when eyelid margin is involved,
the risk for defect is high even with these surgical wide
margins, and the application of reconstructive surgery is
needed. In some cases significant amount of normal tissue
is compromised.15
High-risk SCSC16 is associated with tumour (location,
characteristics) and host factors (immunosuppression,
chronic leukaemia). The mainstay of treatment for high-risk
SCSC is the complete surgical clearance of the lesion with
histological free margins. Radiotherapy is also a treatment
option. More recently, UV-associated skin cancers has
showed sensibility to anti-PD1-mAb treatment.17,18
It has been reported that IFN-α and IFN-γ are been
combined with anti-PD1-mab because the combination
favour the antitumor immunity.19,20
Unmet medical need is identified for patients with locally
advanced or high-risk NMSC or those with indication of
mutilation. The high incidence, morbidity, and mortality of
complex-to treat BCC and SCSC are a major challenge for
Oncology Specialists who have the responsibility to care
these patients.
Immunotherapy could be a prominent non-surgical option
for NMSC. High-risk skin lesions could specially being
benefited from immunotherapy, as well those patients with
indication of mutilation.
Case details
Clinical studies
HeberFERON is a pharmaceutical formulation that contains
co-formulated IFN-α2b and –γ in antiproliferative synergistic
proportions to inhibit tumour cell growth.
The clinical results of patients from open prospective trial;21
phase 2 double-blind randomized studies: InCarbacel-II and
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InCarbacel-III;22 retrospective study23 and ongoing phase IV
trial, InCarbacel-IV) are described.
For evaluation the outcomes were classified as complete
response (CR: total disappearance of the tumour), partial
response (PR: at least a 30 per cent decrease in the sum of
the longest diameter of target lesions) by RECIST,24
objective response (CR+PR), disease control rate (CR+PR +
stable diseases) or progression.
The first study that demonstrated the superiority of
HeberFERON over IFN-α2b was conducted in 40 patients
with surgical BCC, mean age 67-years-old, 57.9 per cent
females. The treatment with HeberFERON (n=19) showed
95 per cent OR vs IFNα-2b with 90 per cent (n=21).
Complete responses were 42.1 per cent and 33.3 per cent in
the HeberFERON and IFNα-2b groups, respectively.
Complete response in the HeberFERON group occurred one
month before than IFN α2b or IFN–γ groups.22
Other clinical trials in patients with advanced NMSC21 and
periocular BCC or SCSC23 have demonstrated the impressive
anti-tumour activity of this IFN formulation. The results are
summarized in Table 1.
The median sustained response in patients with advanced
NMSC, treated with HeberFERON, was 38 months at a 95
per cent confidence interval (22.653.4). The mean survival
was 42.3 months (95 per cent, 29.455.2.21 In the case of
periocular BCC and SCSC, OR was observed in 71.4 per cent
of cases (CR: 47.6 per cent + PR: 23.8 per cent), with a
response duration of 22.6 months.23
Pooled data of patients with BCC from several studies,21-23
and data of ongoing phase IV clinical trial in patients with
BCC of any subtype, size and localization, using the IFNs
combination, were processed. The histological classification
is described in the Figure 1.
There was practically 100 per cent correlation between
clinical and histological CRs (Table 2).
The Figures 2-5 show several pictures of tumours treated
with HeberFERON before and after treatment.
The disease control rate was 98.6 per cent. Only three
progressions were observed, two localized in the face and
the other in the trunk (Table 3).
Discussion
Surgical excision remains the gold standard for the
treatment of NMSC with cure rates as high as 95 per cent.
However, difficult to treat NMSC is a condition without
effective therapy.
Methyl aminolevulinate photodynamic therapy (MAL-PDT)
has demonstrated high cure rates with good cosmetic
outcomes for NMSC. However, in the case of invasive SCSC,
this approach is not recommended.25
HeberFERON produces approximately a 60 per cent and 48
per cent CRs in surgical BCC (recurrent or at diagnostic) and
laBCC, respectively. The duration of these responses is
maintained for five years (manuscript in preparation) and 38
months21, respectively.
Recently two target therapy based on Hh signalling has
been approved for the treatment of patients suffering from
laBCC.26-28 These Hh pathway inhibitors have demonstrated
sub-optimal OR rates of 15 per cent to 60 per cent, with
median durations of response lower than 12 months.
Apparently, HeberFERON showed higher OR rate (87 per
cent, 38 months response duration) than Hh inhibitors for
laBCC21. Additionally, HeberFERON surpass these target
therapies in terms of safety since serious adverse events
have not been detected in the evaluated patients.
The phase 1 ERIVANCE study showed that Vismodegib
promoted a 60.3 per cent OR in laBCC after 24 months
follow-up, 15.5 percent of patients had progressions, and
71.2 per cent developed muscle spasms as most frequent
adverse event (AE).26 In a phase 2 trial Sonidegib induced OR
in 58.0 per cent of patients with laBCC. Between 3.0 per
cent4.0 per cent of patients had grade-3 AEs (fatigue,
muscle spasms, decreased weight).29
Interferons have been shown effectivity in the treatment of
BCC and SCCS.30,31 Preliminary data from Genomic
Laboratory at The Centre for Genetic Engineering and
Biotechnology (CIGB), Havana, showed that HeberFERON is
likely active on tumour cells by promoting apoptosis and
favouring tumour suppressor functions via STAT-1.32
As suggested before21 the apoptosis of BCC cells mediated
by CD95 ligand could be potentiated by the type I and type
II interferons combination. The potentiation of
HeberFERON-induced biological effects has been confirmed
in pharmacodynamics studies.33,34
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There is an important fact that is need to remark. The
evaluation of final clinical and histological response to
HeberFERON is measured 13 weeks after the end of
administration of the product. There are patients that
obtained a CR during the treatment period (3 weeks);
however, other started to have CR after the end of the
treatment.22 This means that antitumor effect is mediated
likely both by direct early effects (induction of apoptosis)
and long-lasting activation of innate and adaptive immune
responses as a result of IFNs actions (dendritic cells
activation, tumour antigen presentation, NK and T-cell
cytotoxicity). The innate and adaptive cellular immune
response plays a key role in surveillance and eradication of
NMSC.35,36 The mechanism of antitumor response in NMSC
patients treated with HeberFERON requires further study.
HeberFERON combined with radiotherapy, chemotherapy,
target therapies or immune check point inhibitors is a
transcendental field of clinical research to be explored and
hopefully will increase the benefits of these patients.
Conclusion
HeberFERON impact positively on the lives of advanced,
high risk or recurrent NMSC patients; and it is an
appropriated therapeutic option for patients suffering from
NMSC, difficult to treat or at risk of surgical aesthetic
complications or recurrent disease.
HeberFERON is part of both the innate and adaptive
immunological response. It plays a key role in immuno-
surveillance and may offer patients an amenable approach
for preventing and treatment of NMSC.
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ACKNOWLEDGEMENTS
The authors wish to thank technicians Ketty Cruz, Grettel
Melo, Ivan Campa MSc and Dr Cimara Bermudez from CIGB
for their assistance in pharmaceutical product preservation
and distribution, Idrian Garcia PhD, from CIDEM, for review
and corrections of the manuscript. The authors received
free HeberFERON from Heber Biotec, Havana, Cuba. The
Ministry of Public Health of Cuba supported the clinical
trials (medical care of the patients, diagnostic procedures,
laboratory test and the other medications).
PEER REVIEW
Not commissioned. Externally peer reviewed.
CONFLICTS OF INTEREST
Authors YDR, ATI, and IBR, are employees of the Center for
Genetic Engineering and Biotechnology, Havana network,
514
[AMJ 2017;10(6):509515]
where HeberFERON is produced. The other authors have no
competing interests.
FUNDING
None
ETHICS COMMITTEE APPROVAL
All the trials were approved by the corresponding
Institutional Ethics Committees.
Figure 1: Histological classification of BCC in those patients treated with HeberFERON
Figure 2: Male patient 48 year-old before treatment (A). Tumour was treated with 10.5 MIU, 2 times a week for 5 weeks at
Policlinic Centro, Santi Spiritus. The treatment was temporally interrupted (during the third week) for one week, due to
local erythema and inflammation. After the interruption the patient continued the treatment to complete d e 9 injections.
CR response was observed at 16 weeks (B)
A B
Figure 3: Nodule ulcerative basal cell carcinoma. Male patient 68 years-old before treatment (A). Tumour was treated with
HeberFERON at Policlinic Cabaiguan, Santi Spiritus, with 10.5 MIU 3 time a week for 3 weeks. CR response at 18 weeks (B)
A B
Figure 4: Nodule ulcerative BCC. Female patient 80 year-old before treatment (A), treated with HeberFERON 3.5 MIU 3
time a week for 3 weeks with CR at 16 weeks (B) by dermatoscopy and histology
A B
Figure 5: Locally infiltrating advanced BCC with destruction of both eyelids in left eye (A). Patient treated with intralesional
HeberFERON concomitant with Cisplatin with CR. Follow-up of 10 year outcome (B)
A B
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Table 1: A summary of the two clinical trials in patients with advanced NMSC treated with HeberFERON
Cohort
Patients
Response rate
Median duration of
response
Serious
adverse events
Locally advanced BCC and SCC. Anasagasti-
Angulo L et al. (2008)Error! Bookmark not defined.
16
87.0%
38.0 months
0%
Periocular BCC and SCC. Garcia-Vega Y et al.
(2013)Error! Bookmark not defined.
21
71.4%
22.6 months
0%
Table 2: Clinical and histological responses BCC subtypes from 215 patients evaluated
Histological
subtypes
Clinical response
Total
Histological
response
Complete
response
Objective
response
Disease control
rate
Progression
Nodular
77 (60.6)
108 (85.0)
125 (98.4)
2 (1.6)
127 (59.1)
52 (68.4)
Superficial
18 (81.8)
21 (95.5)
22 (100.0)
0 (0.0)
22 (10.2)
14 (87.5)
Basosquamous
10 (83.3)
11 (91.7)
11 (91.7)
1 (8.3)
12 (5.6)
7 (77.8)
Nodular-Pigmented
3 (50.0)
5 (83.3)
6 (100.0)
0 (0.0)
6 (2.8)
2 (100.0)
Pigmented
0 (0.0)
3 (75.0)
4 (100.0)
0 (0.0)
4 (1.9)
1 (33.3)
Adenoid-cystic
3 (75.0)
4 (100.0)
4 (100.0)
0 (0.0)
4 (1.9)
2 (50.0)
Sclerosing
3 (100.0)
3 (100.0)
3 (100.0)
0 (0.0)
3 (1.4)
2 (100.0)
Keratotic
2 (66.7)
3 (100.0)
3 (100.0)
0 (0.0)
3 (1.4)
1 (50.0)
Solid ulcerated
0 (0.0)
1 (50.0)
2 (100.0)
0 (0.0)
2 (0.9)
0 (0.0)
Infiltrative
2 (100.0)
2 (100.0)
2 (100.0)
0 (0.0)
2 (0.9)
2 (100.0)
Pleomorphic
0 (0.0)
1 (100.0)
1 (100.0)
0 (0.0)
1 (0.5)
--
Without
classification
15 (51.7)
28 (96.6)
29 (100.0)
0 (0.0)
29 (13.5)
12 (54.5)
Total
133 (61.9)
190 (88.4)
212 (98.6)
3 (1.4)
215 (100.0)
95 (67.9)
Table 3: Clinical and histological responses of histological BCC subtypes from 215 patients evaluated according to tumour
localization.
Tumour
Localization
Clinical response
Total
Histological
response
Complete
response
Objective
response
Disease
control rate
Progression
Face
57 (55.3)
90 (87.4)
101 (98.1)
2 (1.9)
103 (47.9)
38 (63.3)
Trunk
21 (61.8)
27 (79.4)
33 (97.1)
1 (2.9)
34 (15.8)
19 (76.0)
Nose
20 (71.4)
26 (92.9)
28 (100.0)
0 (0.0)
28 (13.0)
13 (65.0)
Arms
14 (70.0)
18 (90.0)
20 (100.0)
0 (0.0)
20 (9.3)
8 (66.7)
Eyelids
7 (77.8)
9 (100.0)
9 (100.0)
0 (0.0)
9 (4.2)
5 (83.3)
Auricular pavilion
7 (87.5)
7 (87.5)
8 (100.0)
0 (0.0)
8 (3.7)
5 (71.4)
Neck
5 (71.4)
7 (100.0)
7 (100.0)
0 (0.0)
7 (3.3)
6 (100.0)
Scalp
2 (33.3)
6 (100.0)
6 (100.0)
0 (0.0)
6 (2.8)
1 (25.0)
Total
133 (61.9)
190 (88.4)
212 (98.6)
3 (1.4)
215 (100.0)
95 (67.9)
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... (10,11,12,13,14,15) De esta forma, el HeberFERON se ha convertido en una opción válida para los pacientes con diagnóstico de carcinoma basal de los párpados con riesgo quirúrgico e implicaciones estéticas. (10,11,12,13,14,15,16) El objetivo de esta investigación fue determinar la respuesta clínica en pacientes con carcinoma basal palpebral tratados con HeberFERON. ...
... Este último resultado coincide con numerosas investigaciones que analizan al CBC de piel avanzado. (3,10,11,14) Esta investigación difiere de los resultados de Anasagasti y otros (15) en relación con el tipo de tumor, con un 93,8 % de lesiones recidivadas. Este mismo porcentaje con tratamiento quirúrgico previo encuentra en la totalidad de los pacientes una extensión tumoral entre los 1,5 y 12,5 cm, este último resultado similar a este trabajo. ...
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... 2021;37(2):e1340 9 Esta obra está bajo una licencia https://creativecom m ons.org/licenses/b y -nc/4.0/deed.es_E S En la atención primaria de salud, hemos utilizado el HeberFERON ® en pacientes con las características anteriores.Hasta el 10 % de los CBC son difíciles de tratar porque son agresivos o producen recurrencias múltiples, por lo que necesitan cirugías invasivas o tratamiento con radioterapia, o requieren considerables excisiones quirúrgicas con reconstrucciones complejas.(7) La excisión quirúrgica es considerada la mejor opción para el tratamiento del CBC, pero en pacientes de alto riesgo o con criterios de mutilación, elHeberFERON ® , una combinación que contiene IFN α2b y IFN γ, en proporciones sinérgicas antiproliferativas que inhiben el crecimiento de células tumorales, solo o en combinación con otros tratamientos como radio o quimioterapia, podría ser considerada la mejor opción terapéutica. ...
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