Sezary syndrome slides

Slides discussing Sezary Syndrome, a rare form of lymphoma.

1. Sezary Syndrome
Bob Marcus
Patient
@bobm

2. Sezary Syndrome Background
Sezary Syndrome is a rare virulent form of lymphoma. It manifests
itself in the skin, blood, and lymph nodes. Because red flaky skin is the most
obvious symptoms, it is often confused with eczema or a more common less
virulent skin cancer, Mycosis Fungoides. Many dermatologists have not seen
Sezary Syndrome and are unaware of the need for a blood test to detect the
condition. If not treated, Sezary Syndrome can be fatal within 3 years.
I was fortunate that my disease was spotted by a Stanford Allergist, Louanne
Tourangeau. For the past 6 years, I have treated for the disease by brilliant
world-class Stanford doctors, Youn Kim and Michael Khodadoust. The
treatments included Romidesin (chemotherapy), Keytruda (immunotherapy),
and currently an experimental drug IPH4102 (targeted therapy).
I am posting these slides to provide information to those who have or might
have Sezary Syndrome. Before being diagnosed, I tried many unsuccessful
treatments for eczema and had several biopsies unsuccessfully looking for
Mycosis Fungoides.

3. Patient Before Treatment
Red Flaky Itchy Skin

4. Patient After Treatment
Sezary Syndrome Basics

5. Sezary Syndrome Definition
From https://ghr.nlm.nih.gov/condition/sezary-syndrome
Sézary syndrome is an aggressive form of a type of blood cancer called
cutaneous T-cell lymphoma. Cutaneous T-cell lymphomas occur when certain
white blood cells, called T cells, become cancerous; these cancers characteristically
affect the skin, causing different types of skin lesions. In Sézary syndrome, the
cancerous T cells, called Sézary cells, are present in the blood, skin, and lymph nodes. A
characteristic of Sézary cells is an abnormally shaped nucleus, described as
cerebriform.
People with Sézary syndrome develop a red, severely itchy rash (erythroderma) that
covers large portions of their body. Sézary cells are found in the rash. However, the
skin cells themselves are not cancerous; the skin problems result when Sézary cells
move from the blood into the skin. People with Sézary syndrome also have enlarged
lymph nodes (lymphadenopathy). Other common signs and symptoms of this condition
include hair loss (alopecia), skin swelling (edema), thickened skin on the palms of the
hands and soles of the feet (palmoplantar keratoderma), abnormalities of the
fingernails and toenails, and lower eyelids that turn outward (ectropion). Some people
with Sézary syndrome are less able to control their body temperature than people
without the condition.”

6. Sezary Syndrome Outline
From https://www.uptodate.com/contents/treatment-of-sezary-syndrome#H346421324
INTRODUCTION
STAGING
CLINICAL APPROACH
INITIAL TREATMENT
•Stratification by stage
◦- Stage IVA (no visceral involvement)
◦- Stage IVB (visceral involvement)
•Preferred initial therapies
◦- Extracorporeal photopheresis (ECP)
◦- Biological response modifiers (BRM)
■Interferons (IFN)
■Retinoids
◦- Low dose methotrexate
◦- Histone deacetylase inhibitors
■Vorinostat
■Romidepsin
■Other HDAC inhibitors
◦- Targeted agents
■Brentuximab vedotin
■Mogamulizumab
ADJUVANT THERAPY
•Skin-directed therapy
•Pruritus
•Prevention of infections
RESPONSE CRITERIA
RELAPSED OR REFRACTORY DISEASE
•Choice of therapy
•Single agent chemotherapy
◦- Pegylated liposomal doxorubicin
◦- Gemcitabine
◦- Purine and pyrimidine analogs
•Other agents
◦- Pralatrexate
◦- Lenalidomide
◦- Alemtuzumab Withdrawn ( https://en.wikipedia.org/wiki/Alemtuzumab )
◦- Bortezomib
◦- Pembrolizumab
•Combination chemotherapy

7. Therapy for Sezary Syndrome
From https://www.clfoundation.org/sezary-syndrome
•Biologic, or immunotherapy, therapy is a treatment used to stimulate a patient’s own immune
system to fight the cancer
•Chemotherapy, a drug given either orally or through an infusion in a vein, to stop the
growth of rapidly dividing cancer cells
•Extracorporeal photopheresis (ECP), a procedure used to expose the blood to ultraviolet light
•Histone deacetylase inhibitors, a class of drugs that cause a chemical change that stops tumor cells
from dividing
•Phototherapy, for example, the drug psoralen and ultraviolet-A light radiation (PUVA) directed
to the skin or skin-directed ultraviolet-B (UVB) or narrow band ultraviolet-B (NBUVB)
•Radiation therapy, which uses high-energy X-rays or other types of radiation to kill cancer cells or
keep them from growing
•Retinoids, which are drugs related to vitamin A and can slow certain types of cancer cells

8. Sezary Syndrome Clinical Treatments
Given the leukemic blood involvement in SS, systemic treatments are generally required. Systemic therapy can be given alone (ie, as
monotherapy), with skin-directed therapy (SDT), or with other systemic therapies (combination therapy with or without SDT).
There is a paucity of controlled clinical trial data to direct the selection of treatment modality in patients with SS. In general, the
following principles apply [2]:
●Treatments are primarily stage-based, but symptoms/tumor burden and the "tempo" of disease activity can vary widely and should
inform treatment choice. Measures of increased tumor burden include the degree of skin infiltration, the presence of skin tumors,
the extent of lymphadenopathy, the burden of circulating tumor cells, and the rate of increase in serum lactate dehydrogenase and
peripheral white blood cell count. As an example, immunomodulatory therapies are preferred for patients with newly diagnosed,
slowly progressive disease. In contrast, chemotherapeutic agents or targeted therapies may be preferred for more immediate
disease control in patients with rapidly progressive disease.
● Medical comorbidities and treatment-related issues (cost, accessibility) affect treatment choice given the chronicity and
recurrent nature of SS. As an example, interferon therapy should be used with caution in patients with concomitant autoimmune
conditions or in solid organ transplant patients.
● Immune-enhancing/preserving agents should be used prior to chemotherapy, if possible.
● Response rates appear to be higher with combination approaches (eg, systemic agent[s] plus SDT).
● Clinicians should monitor for Staphylococcus aureus colonization/skin infection/bacteremia and other infections (fungal, viral) that
can contribute to disease flare and will respond to antibiotics.
● The majority of patients with SS have severe pruritus; topical and systemic anti-pruritics are important adjuncts.
From https://www.uptodate.com/contents/treatment-of-sezary-syndrome

9. Sezary Syndrome Treatments from Dr. Kim
From https://www.ercongressi.it/slides-tcell-2018/7/07-Y.H.Kim.pdf

10. Sezary Syndrome Treatment Guidelines
From https://www.ercongressi.it/slides-tcell-2018/7/07-Y.H.Kim.pdf

11. Modernizing Immunotherapy for CTCL (Dr Kim)
From https://www.clfoundation.org/modernizing-immunotherapy-cutaneous-t-cell-lymphoma

12. Staging Sezary Syndrome
From https://www.uptodate.com/contents/treatment-of-sezary-syndrome
Staging for cutaneous T cell lymphomas is based on evaluation of the
skin (T), lymph nodes (N), viscera (M), and blood (B)
SS is defined by the presence of T4 erythroderma (ie, involvement of
≥80 percent body surface area) plus B2 involvement of peripheral blood
(ie, ≥1000 Sézary cells/microL), and is staged based on the presence of
nodal and/or visceral involvement, as follows:
●Stage IVA1 – No significant lymph node or visceral involvement
●Stage IVA2 – Lymph node involvement, but no visceral involvement
●Stage IVB – Visceral involvement, with or without nodal involvement

13. Sezary Syndrome Summary
Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T cell lymphoma (CTCL) in which a significant
number of circulating malignant (Sézary) cells are observed in the peripheral blood.
● SS is thought to be derived from mature epidermotropic skin homing CD4 positive T cells or central memory T
cells. Cytokines have been implicated in the pathophysiology of SS, but whether cytokine abnormalities are primarily
involved or are secondary processes in the pathogenesis is unclear.
● Patients with SS commonly present with erythroderma and generalized lymphadenopathy developing over weeks
to months. The skin is often pruritic and the patient's quality of life is profoundly affected. Other common clinical
manifestations include opportunistic infections, alopecia, keratoderma, and, less commonly, involvement of other
organs.
● The evaluation of a patient suspected of having SS should include a biopsy of erythrodermic skin, examination of
the peripheral smear for Sézary cells, flow cytometry of the peripheral blood, and an analysis of T cell receptor
(TCR) gene rearrangement by polymerase chain reaction (PCR) or southern blot analysis.
● SS is a clinicopathologic diagnosis based upon the presence of the following three criteria
• Erythroderma defined as erythema covering at least 80 percent body surface area
• A clonal TCR rearrangement in the blood identified by PCR or southern blot analysis
• An absolute Sézary cell count of at least 1000 cells/microL or specific findings on immunophenotype
From https://www.uptodate.com/contents/treatment-of-sezary-syndrome

14. Systemic Therapies for Sezary Syndrome
Systemic therapies for patients with generalized erythroderma include one or a combination of the following:
●Low dose methotrexate – Low dose oral or intravenous methotrexate offers a reasonable response rate, convenience, and
favorable toxicity profile. It may be associated with mucositis, gastrointestinal effects, and myelosuppression; it is a potential
teratogen, and it is occasionally associated with hepatic, renal, pulmonary toxicity.
●Systemic retinoids – Approximately half of patients respond to treatment with systemic retinoids. Retinoids can be used
alone, or more often, in combination with topical steroids, PUVA, or interferon. Retinoids are teratogenic. Common side effects
include hyperlipidemia and central hypothyroidism.
●PUVA (psoralen + ultraviolet A photochemotherapy) – PUVA (psoralen + ultraviolet A photochemotherapy)
results in complete response rates of 30 to 70 percent in patients with generalized erythroderma [26-28]. Treatments are
administered several times a week. Acute complications include erythema, pruritus, blistering, skin dryness, and nausea.
●Interferon – Interferon (IFN) alfa results in overall response rates from 50 to 75 percent. IFN can be combined with other
systemic (eg, retinoids) or skin-directed (topical agents, PUVA, total skin electron beam therapy) therapy. IFN is associated with
significant toxicities including fever, chills, and flu-like symptoms. It should be used with caution in patients with concomitant
autoimmune conditions (eg, rheumatoid arthritis) or following solid organ transplantation.
●Histone deacetylase (HDAC) inhibitors – Approximately one-third of patients will respond to treatment with histone
deacetylase (HDAC) inhibitors. HDAC inhibitors can be combined with other systemic (eg, interferon) or skin-directed (eg, total
skin electron beam therapy) therapy. Side effects include fatigue, nausea, diarrhea, thrombocytopenia, and nonspecific
electrocardiogram effects.
● Brentuximab vedotin – Brentuximab vedotin (BV) is an anti-CD30 antibody conjugated with the tubulin disrupting agent,
monomethyl auristatin E (MMAE). BV can be very effective (especially for tumor stage disease), but patients whose tumors
express very low levels of CD30 (<5 percent) have a lower likelihood of responding to BV. The most common toxicity is
peripheral neuropathy associated with MMAE.
● Alemtuzumab (Discontinued)
From https://www.uptodate.com/contents/treatment-of-sezary-syndrome

15. Low Dose Methotrexate
Low dose oral methotrexate (approximately 5 to 50 mg per week) or intravenous
methotrexate (25 to 50 mg/m
2 once per week) results in overall response rates
(ORRs) of 30 to 50 percent [29]. Methotrexate can be combined with other
systemic (eg, interferon) and/or skin-directed therapy. Common side effects of
low dose methotrexate include mucositis, gastrointestinal effects, and
myelosuppression. Methotrexate can also result in hepatic, renal, and pulmonary
toxicity, and it is an abortifacient that can also induce congenital anomalies if
taken during pregnancy.
From https://www.uptodate.com/contents/treatment-of-sezary-syndrome

16. Systemic Retinoids
Systemic (oral) retinoids result in response rates of 45 to 55 percent (10 to 20 percent complete responses [CR]) depending
upon the dosing and severity of MF [30-35]. Bexarotene is approved by the US Food and Drug Administration (FDA) and
European Medicines Agency's (EMA) for use in patients with advanced MF (stages IIB to IVB) who are refractory to at
least one prior systemic therapy. Isotretinoin and acitretin are commercially available, but not FDA-approved for this
indication Etretinate is available only in Japan.
A phase II/III trial of bexarotene in 94 patients with advanced stage MF (stages IIB to IVB) who were refractory to
conventional therapy reported overall response rates of 45 and 55 percent of patients started on oral doses of 300 and
greater than 300 mg/m
2 per day, respectively [32]. No serious adverse events occurred; the most common toxicities
included hyperlipemia (primarily hypertriglyceridemia, 82 percent), hypercholesterolemia (30 percent), hypothyroidism (29
percent), and headache (20 percent) .
The recommended initial starting dose of bexarotene is 200 to 300 mg/m
2 per day orally. Alternatively, some clinicians start
at very low doses (eg, 150 mg flat dose daily) and titrate up based on tolerance and response. Liver function, serum lipid
levels, thyroid function (serum free T4), and complete blood counts should be monitored in each patient during treatment.
We measure these levels before starting the drug. Lipid levels are then monitored weekly or biweekly until a plateau in the
lipid response and then at four- to eight-week intervals thereafter. A comprehensive metabolic profile, CBC, and serum free
T4 (not TSH) are checked monthly. Bexarotene must be used with caution in patients with hypertriglyceridemia, liver
dysfunction, or risk factors for pancreatitis. Lipid lowering agents and/or thyroid hormone replacement are commonly
required to mediate these side effects of bexarotene; however, patients taking bexarotene should not be treated with
gemfibrozil because coadministration results in increased serum levels of bexarotene. Omega-3-fatty acids may be initiated
prior to treatment with bexarotene to lessen the hypertriglyceridemia.
Most toxicities due to systemic retinoids are reversible after cessation of therapy. The most common adverse effects of
retinoids include photosensitivity, xerosis, myalgia, arthralgia, headaches, and impaired night vision. Retinoids have
potential hepatotoxic and hyperlipidemic effects, necessitating monitoring. Patients receiving treatment with oral
bexarotene are also at increased risk for hypertriglyceridemia and central hypothyroidism, and may require anti-lipidemic
and thyroid replacement therapy
From https://www.uptodate.com/contents/treatment-of-sezary-syndrome

17. Bexarotene (Targretin)
References: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322887/
and https://en.wikipedia.org/wiki/Bexarotene
From https://www.researchgate.net/publication/

18. Brentuximab Vedotin
 Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody conjugated with monomethyl auristatin E by a protease-
cleavable linker and has established activity in lymphomas that express CD30. It has been approved by the US Food and
Drug Administration (FDA) for treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma. BV is an
option for patients with MF that has relapsed after radiation therapy or systemic methotrexate, and for patients with
generalized tumors (eg, >10 percent body surface area).  
Studies that have evaluated use of BV in MF/SS include the following:
● In a phase II study, 33 patients were treated with BV (1.8 mg/kg) every three weeks for eight cycles, and those who were
benefiting and tolerating treatment could receive up to eight additional cycles (16 total cycles) [38]. The ORR was 70 percent,
including responses in skin, blood, and extracutaneous compartments. Responses were observed in patients with all levels of
CD30 expression, but were significantly lower in those with CD30 expression <5 percent. A reduction in skin tumor burden
measured by mSWAT score decreased by at least 90 percent in one-quarter of patients.
Peripheral neuropathy was the primary toxicity and was observed in 66 percent of patients. Other common toxicities were
fatigue (47 percent) and nausea (28 percent). An international, open-label trial randomly assigned 128 patients with CD30
expressing MF (97 patients) or primary cutaneous ALCL to BV versus the physician’s choice (PC) of bexarotene or
methotrexate [39]. Compared with PC, BV achieved superior rates of:
• OR that lasted at least four months (ORR4) – 56 versus 13 percent
• CR – 16 versus 2 percent
• Median progression-free survival – 17 versus 4 months
• Symptomatic relief (measured by Skindex-29 score) – 28 versus 9
There were comparable rates of grade 3/4 adverse events, but higher rates of peripheral neuropathy (any grade) with BV (67
versus 6 percent).
From https://www.uptodate.com/contents/treatment-of-sezary-syndrome

19. Brentuximab Vedotin
Reference: http://www.seattlegenetics.com/pipeline/brentuximab-vedotin
From http://clincancerres.aacrjournals.org/content/19/1/22

20. Interferon
Interferon (IFN) alfa is used primarily for the palliative management of relapsed or refractory advanced
disease with overall response rates from 53 to 74 percent (21 to 35 percent CR) . However, the majority of
patients will relapse during maintenance therapy.
IFN may be administered alone or, more commonly, in combination with topical or other systemic treatments
[. As an example, the combination of IFN alfa plus PUVA results in CR and partial response (PR) rates of 75
to 80 percent and 6 to 20 percent, respectively, in patients with generalized patch/plaque disease (stages IB
and IIA). Although the clinical response and response duration appear to be better with the combined
regimen of PUVA and IFN, as compared with either treatment alone, randomized prospective clinical trials
are needed to confirm this impression .
An additional benefit of combined therapy may be the suppression of anti-IFN-alfa antibody formation. None
of the 24 patients with MF assayed in a clinical study developed antibodies, compared with a reported
incidence of 4 to 46 percent in a variety of other cancer settings.
Administration of IFN alfa for MF is usually initiated at a dose of 3 to 5 million units SQ given three times a
week. This dose is gradually increased, depending on the clinical response and the severity of adverse effects.
For a regimen combining IFN and PUVA, the two treatments are initiated concurrently, each given three
times per week. When a patient's skin clears completely, IFN is stopped and maintenance therapy with PUVA
treatment at a reduced frequency is begun.
From https://www.uptodate.com/contents/treatment-of-sezary-syndrome

21. Romidepsin
Romidepsin (also known as depsipeptide) is a histone deacetylase (HDAC) inhibitor with activity in
cutaneous T cell lymphoma (CTCL) [47]. It has demonstrated an overall response (OR) rate of 35
percent in two separate studies and is approved by the US Food and Drug Administration for the
treatment of CTCL in patients with progressive, persistent, or recurrent disease on or following at
least one prior systemic therapy.
Romidepsin is administered as a single agent at a dose of 14 mg/m
2 administered by intravenous
infusion over four hours on days 1, 8, and 15 of a 28-day cycle. Full prescribing information is available
separately .
Several treatment-emergent changes in electrocardiograms (ECGs) (including T-wave and ST-segment
changes) have been reported in clinical studies with romidepsin, but have not been shown to be
clinically significant [49,51,52]. In patients with congenital long QT syndrome, patients with a history of
significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products
that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be
considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during
treatment. Romidepsin is metabolized by CYP3A4. Co-administration of strong CYP3A4 inhibitors or
potent CYP3A4 inducers should be avoided if possible.
Potassium and magnesium levels should be in the normal range before drug administration. There is no
required monitoring of ECGs in patients who do not have the above risk factors.
From https://www.uptodate.com/contents/treatment-of-sezary-syndrome

22. Romidepsin (Istodax)
From http://drugapprovalsint.com/romidepsin/

23. Vorinostat, Alemtuzumab, and PUVA Therapy
Vorinostat — (Inferior to Romidepsin) Vorinostat is an orally active histone deacetylase
(HDAC) inhibitor, with PR rates in MF of 30 percent . It is approved by the FDA for the
treatment of CTCL in patients with progressive, persistent, or recurrent disease after
two systemic therapies..
Toxicities of vorinostat included diarrhea (46 percent), fatigue (49 percent), nausea (43
percent), anorexia (26 percent), and dysgeusia (24 percent). Hematologic abnormalities
included anemia, thrombocytopenia (22 percent), and neutropenia, most of which were
grade 1 or 2 in severity. The most common severe adverse event was pulmonary
embolus, seen in four patients (5 percent). Patients enrolled in clinical studies were also
instructed to drink at least 2 liters of fluid daily to avoid dehydration.
Alemtuzumab —(Withdrawn) The anti-CD52 monoclonal antibody alemtuzumab has
demonstrated OR rates of up to 55 percen. Alemtuzumab is only appropriate for
patients with erythrodermic MF with or without blood involvement (stages III and IVA).
Patients with bulky lymph nodes are unlikely to respond.
PUVA therapy — PUVA (psoralen + ultraviolet A photochemotherapy) results in CR
rates of 30 to 70 percent in patients with generalized erythroderma . In such cases,
PUVA must be started at a low dose followed by a very slow and cautious increase of
UVA dose to avoid phototoxic reactions. Despite a good clinical response with PUVA
alone, the majority of the patients relapse during maintenance therapy.  Extracorporeal
photopheresis (ECP) is a method of delivering PUVA (psoralen + ultraviolet A
photochemotherapy) systemically by using an extracorporeal technique
From https://www.uptodate.com/contents/treatment-of-sezary-syndrome

24. Sezary Treatments 2015
From https://onlinelibrary.wiley.com/doi/pdf/10.1111/ddg.12900
Altered signaling pathways and dysregulated molecules in Sézary cells that might represent new therapeutic targets.

25. Mogamulazib
Reference: http://www.cancernetwork.com/skin-cancer-nonmelanoma/mogamulizumab-approved-two-rare-types-cutaneous-t-cell-lymphoma
From http://www.lymphomation.org/mogo.htm

26. Targeting TNFR2 by Dr. Khodadoust
Background: Tumor necrosis factor receptor 2 (TNFR2, or TNFRSF1B) is a lymphoid marker of the most potent regulatory T
cell (Treg) subtype and a commonly expressed oncogene in human tumors. TNFR2 Tregs are also enriched in the tumor
microenvironment. Recently, TNFR2 antagonistic antibodies have been made that inhibit NFkB-driven growth through the
TNFR2 receptor. These antagonists have shown both Treg and tumor inhibition with specificity for the tumor
microenvironment (Science Signaling 2017).
Cutaneous T cell lymphoma (CTCL) currently has few effective treatments. Recent data shows that TNFR2 is a candidate
oncogene in CTCL with recurrent point mutations and gain of function alteration of TNFR2, resulting in abnormal expression
of TNFR2 on CD4+CD26- tumor cells (Nature Genetics 2015). We studied the effectiveness of TNFR2 antagonistic antibodies
for direct CTCL tumor killing, direct Treg killing and ability to unleash effector T cell (Teffector) proliferation. Stage IV
CTCL (Sézary syndrome) subjects with failure on diverse drug regimens were recruited to understand in vitro the effectiveness
of adding TNFR2 antagonism to the treatment regimen to restore immune balance.
Conclusions: TNFR2 is a recurrent genomic gain alteration in CTCL that can potentially be targeted to directly stop the
growth of tumor cells by antibody-induced cell death. The recently discovered TNFR2 oncogene is also expressed on many
other human tumor cells, including in colon cancer, multiple myeloma, renal cell carcinoma, Hodgkin’s lymphoma, ovarian
cancer, and non-cutaneous T cell lymphomas. This feature makes TNFR2 an advantageous molecular target for direct tumor
killing. TNFR2 antagonism also provides the ability to eliminate the potent Tregs of the tumor microenvironment and unleash
Teffector proliferation.
From http://cancerimmunolres.aacrjournals.org/content/6/9_Supplement/B18

27. Pembro by Dr. Khodadoust
From https://ash.confex.com/ash/2018/webprogram/Paper117244.html

28. P38 as a Target
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289446/

29. Sezary Syndrome Chapter
From https://tinyurl.com/y4o3hxmr

30. Innate IPH4102
From https://www.ncbi.nlm.nih.gov/pubmed/31253572

31. Innate IPH4102
“KIR3DL2 is an inhibitory receptor of the KIR family, expressed by
approximately 65% of patients across all CTCL subtypes and expressed by
up to 85% of certain aggressive CTCL subtypes, in particular, Sézary
syndrome and transformed mycosis fungoides (tMF). KIR3DL2 has a restricted
expression on normal tissues.”
From https://www.innate-pharma.com/en/pipeline/iph4102-first-class-anti-kir3dl2-mab
Reference: http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.TPS2591

32. Innate IPH4102 (continued)
Background: KIR3DL2 is consistently expressed in all subtypes of Cutaneous
T-cell Lymphomas (CTCL), irrespectively of disease clinical stage, with the
greatest expression in Sézary Syndrome (SS) and transformed Mycosis
Fungoides (MF), two subsets with high unmet need. KIR3DL2 belongs to the
killer immunoglobulin (Ig)-like receptor (KIRs) family expressed on minor
populations of NK, CD8 and CD4 T cells. IPH4102 is a first-in-class anti-
KIR3DL2 monoclonal antibody (mAb). It depletes selectively KIR3DL2-
expressing cells. Its modes of action include Antibody-Dependent Cell-
Cytoxicity (ADCC) and –Phagocytosis (ADCP). IPH4102 has potent efficacy in
non-clinical models, in particular ex vivo autologous assays using primary CTCL
cells
\http://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.TPS2591

33. Innate IPH4102 (continued)
\
From www.innate-pharma.com/sites/default/files/180928_bagot_et_al_st_gallen_eortc_vfinal.pdf

34. Sezary Outline
From https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immune-checkpoint-inhibitor

35. Cibersoft
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895181/figure/F1/

36. Sezary Pathways
From: http://pathwaymaps.com/static/maps/720_map.png

37. From: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964925/
Microbiomes and Cancer Treatment (Pharmacomicrobiomics)

38. Microbiomes and Cancer Yreatment 2 (Pharmacomicrobiomics)
From: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964925/

39. Immunotherapy Targets
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883082/

40. Immunotherapy Target Network Diagram
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883082/

41. Immunotherapy Target Network Explained
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883082/

42. New Drugs for Sezary Syndrome 2018
From http://cco.amegroups.com/article/viewFile/22621/21791

43. Small Molecules for Immunotherapy
https://register.healthtech.com/reg?DCH19&ID=18465&CO=0
First-generation cancer immunotherapy agents being developed or approved were either engineered T cells targeting tumors or antibody-
based biologics targeting the immune checkpoint cascade. However, novel second and third-generation drugs that are in preclinical or early-
stage clinical development are small molecules that act on intracellular targets and receptors affecting immuno-modulatory pathways in
cancer. Cambridge Healthtech Institute's 3rd Annual Small Molecules for Cancer Immunotherapy conference, taking place in San
Diego from April 9-10, 2019, brings together discovery chemists and biologists to talk about these new intracellular oncology targets and
immuno-modulatory small molecule inhibitors that are being developed to act alone or in combination with existing treatments. IDO1, USP7,
STING, TIM-3, VISTA, LAG-3, KIR, bromodomains are examples of some oncology targets that are being actively pursued by small molecule
drugs. The development of programs around these targets and discussions on translational challenges, response rates, drug resistance and
safety will certainly be covered in this conference.
References
IDO1 https://en.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase
USP7 https://en.wikipedia.org/wiki/USP7
STING https://cen.acs.org/articles/96/i9/STING-fever-sweeping-through-cancer.html
https://www.technologynetworks.com/cancer-research/blog/the-sting-pathway-and-cancer-305362
TIM-3 https://en.wikipedia.org/wiki/HAVCR2
http://cancerimmunolres.aacrjournals.org/content/2/5/393
VISTA https://en.wikipedia.org/wiki/VISTA_(protein)
LAG3 https://en.wikipedia.org/wiki/LAG3
KIR https://www.onclive.com/publications/oncology-live/2017/vol-18-no-01/targeting-kir-opens-door-to-promising-immunotherapy-
combos
Bromodomain https://en.wikipedia.org/wiki/Bromodomain
Addition References
TIGIT Helios FCRL3 expressed in Sezary patients
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358509/
Loss of ZEB1 in Sezary Syndrome patients
https://www.nature.com/articles/s41419-018-1212-7
https://www.genecards.org/cgi-bin/carddisp.pl?gene=ZEB1
https://en.wikipedia.org/wiki/ZEB1
https://www.researchgate.net/publication/
329429259_Loss_of_the_candidate_tumor_suppressor_ZEB1_TCF8_ZFHX1A_in_Sezary_syndrome
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281581/

44. ZEB1 and ZEB2
From https://journals.lww.com/hemasphere/Fulltext/2018/06000/ZEB_Proteins_in_Leukemia___Friends,_Foes,_or.7.aspx

45. Regulator T-Cells
From https://en.wikipedia.org/wiki/Regulatory_T_cell

46. CAILS Evaluation
From https://seekingalpha.com/article/4209955-trillium-therapeutics-updates-lead-lymphoma-trials

47. Latest Results (2018)

48. Sezary Genomic Profiling
From https://www.nature.com/articles/ng.3444
Sézary syndrome is a rare leukemic form of cutaneous T cell lymphoma
characterized by generalized redness, scaling, itching and increased numbers of
circulating atypical T lymphocytes. It is rarely curable, with poor prognosis. Here we
present a multiplatform genomic analysis of 37 patients with Sézary syndrome that
implicates dysregulation of cell cycle checkpoint and T cell signaling. Frequent
somatic alterations were identified in TP53, CARD11, CCR4, PLCG1, CDKN2A, ARID1A,
RPS6KA1 and ZEB1. Activating CCR4 and CARD11 mutations were detected in nearly
one-third of patients. ZEB1, encoding a transcription repressor essential for T cell
differentiation, was deleted in over one-half of patients. IL32 and IL2RG were
overexpressed in nearly all cases. Our results demonstrate profound disruption of
key signaling pathways in Sézary syndrome and suggest potential targets for new
therapies.

49. Clinical Trials 2/19
From http://cco.amegroups.com/article/viewFile/22621/21791

50. Expressions of Proteins in Sezary
From https://www.ejcancer.com/article/S0959-8049(18)31162-6/abstract

51. TIGIT and Helios Expression in Sezary
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358509/

52. Divergent LAG-3 vs BTLA, TIGIT, and FCRL3 Expression
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358509/

53. BTLA Expression
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358509/

54. LAG-3 Expression
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358509/

55. TIGIT Expression
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358509/

56. FCLR3 Expression
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358509/

57. Divergent Expression Conclusion
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358509/

58. Divergent Expression Conclusion(continued)
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358509/

59. Divergent Expression Conclusion(continued)
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358509/

60. Clinical Trial Keytruda and LAG-3
From https://www.mrknewsroom.com/news-release/oncology/early-phase-1-data-mercks-oncology-pipeline-investigational-anti-lag-3-therapy
From https://www.cancer.gov/publications/dictionaries/cancer-drug/def/anti-lag3-monoclonal-antibody-mk-4280

61. Anti-LAG-3 Therapy
From https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?id=NCI-2017-02413&r=1

62. Anti-LAG-3 + Anti-PD1 Therapy
From https://medium.com/@Innoplexus/whats-next-in-immune-checkpoints-is-lag-3-emerging-as-a-potential-combination-partner-with-pd-1-aed11b56fb4b

63. Anti-LAG-3 + Ant-PD-1 Therapy
From https://seekingalpha.com/article/4078906-bristol-myers-squibb-bmy-investor-presentation-slideshow

64. Anti-TIGIT Therapy
From https://www.mrknewsroom.com/news-release/oncology/early-phase-1-data-mercks-oncology-pipeline-investigational-anti-lag-3-therapy

65. Anti-TIGIT Therapy
From https://www.onclive.com/publications/oncology-live/2017/vol-18-no-03/tigit-emerges-as-new-target-for-immune-checkpoint-blockade-strategies

66. LAG-3, TIGIT, and Keytruda
From https://www.mrknewsroom.com/news-release/oncology/early-phase-1-data-mercks-oncology-pipeline-investigational-anti-lag-3-therapy

67. Corvus CPI-818
From https://www.corvuspharma.com/file.cfm/23/docs/2019_TCL-Forum_Poster-CPI-818.pdf

68. Corvus CPI-818
From https://www.corvuspharma.com/file.cfm/23/docs/2019_TCL-Forum_Poster-CPI-818.pdf

69. Corvus CPI-818
From https://www.corvuspharma.com/file.cfm/23/docs/2019_TCL-Forum_Poster-CPI-818.pdf

70. TTI-621 (SIRPαFc) Blocking the CD47 "Do Not Eat" Signal
From http://www.bloodjournal.org/content/130/Suppl_1/4076?sso-checked=true

71. TTI-621 (SIRPαFc) Update 4/18
From https://globenewswire.com/news-release/2018/04/10/1467626/0/en/Trillium-Therapeutics-Provides-Update-on-Its-TTI-621-and-TTI-622-Clinical-Programs.html

72. CTLA-4
From https://www.immunooncologyhcp.bmsinformation.com/antitumor-immunity/pathways/CTLA-4-pathway

73. Gene Expression Profiling
From https://www.tandfonline.com/doi/full/10.1080/2162402X.2018.1467856?src=recsys

74. NeoAntigens
From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203688/

75. NeoAntigens
From https://www.nature.com/articles/d41586-017-08706-3
Three independent studies over the past four years have reported on the experience of roughly
two dozen people with melanoma, who were given experimental vaccines containing cocktails
of neoantigens. After receiving the vaccines, all the participants made immune cells known as T
cells that could specifically target their cancers.
Most remarkably, each person received a unique set of neoantigens. The researchers analysed
individual tumour genomes and the patients’ immune systems to make an optimal mix of
antigens.

76. Gritstone NeoAntigens
From https://gritstoneoncology.com/scientific-platform/

77. Gritstone Edge
From https://gritstoneoncology.com/scientific-platform/

78. NeoAntigens Article
From https://www.ncbi.nlm.nih.gov/pubmed/29751996

79. Immunotherapy attacking NeoAntigens
From https://www.sciencedirect.com/science/article/pii/S1044532315000731

80. Ucart and Long-Acting Interleukin-7 Combination Therapy
From https://ash.confex.com/ash/2018/webprogram/Paper119375.html

81. New Developments in Immunotherapy for Lymphoma
From https://pdfs.semanticscholar.org/e0e4/6d6e82122fe8608971e2444a26d835c3e107.pdf

82. Cancer Vaccine from Neon
From https://immuno-oncologynews.com/neo-pv-01/

83. Corvus CPI-818
From https://www.corvuspharma.com/file.cfm/23/docs/2019_TCL-Forum_Poster-CPI-818.pdf

84. References

85. References
•103 links to recent research (Subscription needed)
https://www.uptodate.com/contents/treatment-of-sezary-syndrome#H346421324
•55 Recent References (2018)
https://www.tandfonline.com/doi/full/10.1080/10428194.2018.1564827
• Microbiome and Immunotherapy
https://www.forbes.com/sites/victoriaforster/2019/02/27/fiber-intake-and-probiotics-may-affect-
response-to-immunotherapy-in-cancer-patients/#4dbad13a5512
• Parker Center for Immunotherapy
https://www.parkerici.org/our-model/
• Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome
https://academic.oup.com/annonc/article/28/10/2517/4004847