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TOWER study published in 2017. In this multi-institutional phase 3 trial, patients
over the age of 18, who were refractory to primary induction chemotherapy or to
salvage chemotherapy, had a rst relapse with the rst remission lasting less than
12months, a second or more relapse, or relapse at any time after allogeneic stem
cell transplantation and were randomized to either blinatumomab or standard of
care. The TOWER study demonstrated improved median OS with blinatumomab
versus standard of care (7.7 vs. 4.0months). Event-free survival was also higher
with blinatumomab than standard of care (six-month estimates, 31% vs. 12%). And
nally, remission rates within 12weeks after treatment were signicantly higher in
the blinatumomab group than in the standard of care group. Currently approved
indications for blinatumomab are outlined in Table3.1.
Teclistamab-cqyx is the sole BiTE that is approved in the treatment of MM.It is
a BiTE targeted against B-cell maturation antigen (BCMA) and CD3 (Fig.3.1).
Approval was achieved via the MajesTEC-1 trial in 2022. In this study, patients with
R/R multiple myeloma after at least three systemic therapies, of which must have
included triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody, were treated with teclistamab. With a median follow- up of 14.1months, the OR rate was 63.0%, with 39.4% having a CR.A total of
26.7% of patients were found to have MRD negativity. The median duration of
response was 18.4months with the median duration of progression-free survival of
11.3months (Moreau etal., 2022). Currently approved indications for teclistamab
are outlined in Table3.1.
Tebentafusp-tebn is currently the only BiTE approved for treatment of a solid
tumor, uveal melanoma. More specically, it is used for unresectable or metastatic
uveal melanoma. It uniquely binds to gp100 loaded into the HLA-A*02:01 molecule and brings it into proximity with CD3-expressing cells. It rst gained approval
in January 2022 based upon a phase 3 clinical trial demonstrating improved OS at 1
year (73% vs. 59% in control) (Nathan etal., 2021). Currently approved indications
for tebentafusp-tebn are outlined in Table3.1.
R. C. Godby etal.
Adverse Events andLimitations
Cytokine Release Syndrome (CRS)
After administration of BiTE products, there is potential for rapid activation and
cytotoxic activity resulting in large amounts of cytokine release (van de Donk &
Zweegman, 2023). Clinically, this may manifest with fevers, hypotension, and
hypoxia which are used to grade the CRS in a similar fashion to that of CAR-T and
subsequently guide treatment (Lee et al., 2019; NCCN, 2023; van de Donk &
Zweegman, 2023). This seems to be dependent on route of administration and pharmacokinetics of the product, with the highest rates occurring shortly after relatively
larger intravenous dosing (van de Donk & Zweegman, 2023). Each therapy has
3 Immunotherapies forCancer: Bi-specic T Cell Engagers (BiTEs)
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product-specic recommendations for management of CRS, but in addition to supportive care, treatments if clinically warranted may include anti-IL6 therapy (e.g.,
tocilizumab) and dexamethasone (NCCN, 2023; van de Donk & Zweegman, 2023).
31
Immune Effector Cell-Associated Neurotoxicity
Syndrome (ICANS)
After administration of BiTE products, there is potential for rapid activation and
cytotoxic activity resulting in large amounts of cytokine release that may also disrupt the blood-brain barrier (van de Donk & Zweegman, 2023). Clinically, this may
manifest with depressed consciousness, seizures, motor changes, and cerebral
edema which are used to grade the ICANS in a similar fashion to that of CAR-T and
subsequently guide treatment (Lee etal., 2019; Santomasso etal., 2021; NCCN,
2023). This occurs relatively infrequently for products not targeting CD19 (van de
Donk & Zweegman, 2023). Each therapy has product-specic recommendations for
management of ICANS, but in addition to supportive care, treatments if clinically
warranted may include dexamethasone with the possible addition of antiepileptics;
anti-IL6 therapy is usually added only for the simultaneous presence of CRS
(NCCN, 2023; van de Donk & Zweegman, 2023).
Infections
Patients receiving BiTE therapies often experience infections that can arise from
various etiologies. By the time patients are eligible for BiTEs, they have already
been exposed to cytotoxic chemotherapy, and many BiTEs may lead to T cell
exhaustion. Furthermore, another consequence of many approved BiTE products is
hypogammaglobulinemia, predisposing to additional infectious complications (van
de Donk & Zweegman, 2023).
Future Directions
Although BiTEs have been around for years, a rapidly growing list of indications
with clear efcacy solidies this technology as a cornerstone of hematology and
oncology treatments in the future. There are several ongoing studies and ideas for
technological advancements to further expand this armamentarium and enhance
outcomes. For instance, from tri-specic engagers and sequencing of engagers to
alternative and/or combinatorial targets of cell engagement in addition to T cells are
interesting areas of research. Additionally, given that these “off-the-shelf” products
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R. C. Godby etal.
have logistical advantages over CAR-T therapies and obviate the need for additional
cytotoxic chemotherapy, they will continue to further the elds of both hematology
and oncology by harnessing the potential of the immune system.
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Blood and Marrow Transplantation, 25, 625–638.
Moreau, P., Garfall, A.L., van de Donk, N.W. C.J., et al. (2022). Teclistamab in relapsed or
refractory multiple myeloma. The New England Journal of Medicine, 387, 495–505. https://
doi.org/10.1056/nejmoa2203478
Nathan, P., Hassel, J.C., Rutkowski, P., etal. (2021). Overall survival benet with tebentafusp in
metastatic uveal melanoma. The New England Journal of Medicine, 385, 1196–1206. https://
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Chapter 4
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Tumor-Inltrating Lymphocyte (TIL)
Therapy
JeffreyE.Johnson, VelvetR.Van Ryan, andArkadiuszZ.Dudek
Abstract Since T cells can recognize tumor-associated antigens and eliminate
cancer cells, preclinical and clinical developments of therapy have been leveraging
on the use of autologous tumor-inltrating lymphocytes (TILs). Target metastatic
tumor is excised from patient by trained surgeon and then transferred to laboratory,
where is cut into small fragments. Lymphocytes are then enriched in culture with
interleukin 2 and after several days propagated in rapid expansion phase. When TIL
product is ready, patient receives lymphodepleting chemotherapy, and then TILs are
infused followed by treatment with high-dose interleukin 2. Therapy with TIL has
shown to be an effective treatment strategy in melanoma, even after melanoma progression following immune checkpoint inhibitor therapy with remarkable responses
and improvement of progression-free survival. Recently, genetically modied TILs
have been tested with a goal to further improve clinical activity.
Keywords Tumor-inltrating lymphocytes · Interleukin 2 · Infrastructure for TIL
therapy · Melanoma · Lymphodepleting therapy
Knowledge that T cells can recognize tumor-associated antigens and in turn cause
elimination of melanoma cells led to the idea of tumor treatment by infusion of
immunized lymphoid cells (Rosenberg etal., 1982). Success of the cancer treatment
was dependent on the dose of infused sensitized to tumor cells, and therefore expansion of immune cells by interleukin-2 (IL-2) was introduced and cured of up to 93%
of animals (Eberlein etal., 1982). Around the same time, the discovery that suppressive T cells will interfere with adoptive therapy led to the use of cyclophosphamide
prior to infusion of immunized cells to decrease suppressive T cell population
J. E. Johnson · V. R. Van Ryan
Department of Surgery, Mayo Clinic, Rochester, MN, USA
A. Z. Dudek (*)
Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
e-mail: dudek.arkadiusz@mayo.edu
H. Dong, S. N. Markovic (eds.), The Basics of Cancer Immunotherapy,
https://doi.org/10.1007/978-3-031-59475-5_4
33© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
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J. E. Johnson et al.
(North, 1982). In 1986, Rosenberg etal. published pivotal paper demonstrating that
tumor-inltrating lymphocytes (TILs) grown from and expanded in IL-2, when
injected to animals pretreated with cyclophosphamide and treated with IL-2 after
infusion, were 50–100 times more effective than lymphokine-activated killer cells
(Rosenberg etal., 1986). This discovery initiated the development of TIL for therapy of human patients with cancer. Optimization of culture techniques of TIL
(Dudley etal., 2003) led to study of 35 patients with metastatic melanoma treated
with lymphodepleting regimen of 2days of cyclophosphamide and 5days of udarabine, infusion of TIL, and then high-dose IL-2. This resulted in 51% clinical
response rates including three complete responses (Dudley etal., 2005). Activity of
TIL therapy was conrmed in other studies (Besser etal., 2010; Radvanyi etal.,
2012). With increasing number of patients treated with TIL, knowledge of best sur-
gical techniques and metastatic sites from which to harvest TIL was gained (Goff
etal., 2010).
Multi-institution phase 2 study of centrally manufactured TIL product in previously treated patients with immune checkpoint inhibitors for metastatic melanoma
demonstrated that TIL can induce tumor response rate of 41% in this patient population (Sarnaik et al., 2021). With additional cohorts, pooled analysis of patients
treated with TIL, lileucel product, conrmed overall response rate of 31.4% with
41.7% of responses lasting at least 18months (Chesney etal., 2022).
In randomized, phase 3, multicenter study outcomes of treatment of patients with
unresectable or metastatic melanoma treated with TIL were compared to anticytotoxic T-lymphocyte antigen 4 therapy with ipilimumab. Median progressionfree survival was superior inpatients receiving TIL (7.2months) versus ipilimumab
(3.1months) (Rohaan etal., 2022).
Further research was focused on prolongation of TIL persistence (Krishna etal.,
2020), increased activity (Chamberlain etal., 2022), and preservation from exhaus-
tive phenotype (Woroniecka etal., 2020).
TIL therapy requires a multidisciplinary approach. Medical oncologists, surgeons, advanced practice providers, registered nurses, and technicians familiar with
the multiple facets of TIL therapy are integral. Overall, having the lymphodepleting
treatment, infusion of TIL, and high-dose IL-2 on an oncology or intensive care unit
is optimal.
Appropriate patient selection is critical. Patients need to have a performance
status of 0–1 with low cardiac and pulmonary comorbidities (Sarnaik etal., 2021;
Rohaan etal., 2022). Cardiac stress testing and pulmonary function tests can aid in
identifying acceptable respective organ function. Untreated, active brain metastases
are contraindicated (Sarnaik etal., 2021; Rohaan etal., 2022).
In addition, there are a number of surgical specimen considerations that must be
considered for patient’s selection as well as ensuring an adequate sample for production of the cell therapy product. Multidisciplinary collaboration with surgical
oncologists, other subspecialty surgeons, radiologists, and medical oncologists is
needed to select patients who will tolerate anesthesia, recover quickly from surgery
4 Tumor-Inltrating Lymphocyte (TIL) Therapy
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35
to allow for treatment within 3–4weeks, and have a lesion of sufcient size, character, and accessibility to allow for surgical resection. Patient being considered for
surgery will often have a range of comorbidities and diminished functional status,
often related to progressive disease and receipt of multiple lines of systemic therapy
prior to consideration for TIL cell therapy, which must be considered in surgical
planning.
Although it depends on manufacture or clinical study criteria, generally tumor
tissue measuring 1–4cm in size is required for isolation in expansion of sufcient
TILs (Goff etal., 2010; Mullinax etal., 2022). Anatomic locations that minimize
morbidity and allow for outpatient surgery are favored, such as tumors involving the
skin and supercial tissues or accessible lymph node basins. Tumors involving visceral organs can also be used, and minimally invasive surgery is favored to speed
recovery time. Consideration for visceral surgery, for example, liver or lung resections, requires careful patient selection and discussion with surgeons experienced in
performing surgery in those areas. Tumors should also have sufcient viable cellularity to allow for culture, excluding small or necrotic tumors. Additionally, tumors
with a risk of bacterial contamination due to extrinsic exposure (e.g., ulceration,
aerodigestive tract, genital organs) cannot be used due to risk of contamination,
precluding use of the cultured cell product (Mullinax etal., 2022).
Early studies had a signicant proportion of patients initiating the TIL procurement process but ultimately not receiving therapy. Since then, better patient selection, streamlined workow, and improved production protocols have increased
likelihood of completing TIL production leading to infusion to above 90% (Chesney
etal., 2022; Mullinax etal., 2022). Patients may have a number of anatomic sites
involved with metastatic cancer, and generally any site of disease may be used as all
tissues are able to yield TILs and tumor resection site does not affect systemic efcacy of TIL therapy (Goff etal., 2010; Sarnaik etal., 2021). However, sites from
secondary lymphoid organs or sites with high non-tumor reactive lymphocytes
(e.g., bowel) may result in lower tumor-specic TIL yield (Goff etal., 2010).
Once a metastatic tumor has been excised, the surgeon places the tumor in the
sterile eld to select tumor areas avoiding necrosis or non-tumor-involved tissue
and selecting well-vascularized viable tumor. It is vital that all tissue handling
remain under sterile conditions to prevent contamination. Intraoperative pathology
review to conrm presence of tumor and inltrating lymphocytes may be used as
needed. The prosected tissue is placed into a sealed sterile media container and
transported to a Good Manufacturing (GMP) laboratory (Mullinax et al., 2022).
GMP labs follow strict US Food and Drug Administration regulations to ensure
products are consistently produced and controlled (Chu etal., 2023). The laboratory
expands the lymphocytes exvivo in a medium that includes IL-2 (Andersen etal.,
2016; Sarnaik etal., 2021; Ernst & Giubellino, 2022). Once the cell proliferation
goal has been met, the cells are cryopreserved for later use.
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J. E. Johnson et al.
Upon completion of TIL expansion and transfer to treatment site, the patient can
begin lymphodepletion therapy. It is important to have an oncology team of experienced physicians, advanced practice providers, and nurses to safely care for the
patient and manage the ensuing side effects. The more common side effects include
bone marrow suppression, electrolyte imbalances, nausea, vomiting, and diarrhea
(Rohaan etal., 2022). These patients may need blood product transfusions, electrolyte replacement, and additional medical management during this time.
Within 24h of the completion of the lymphodepletion regimen, the TIL cells are
infused. The patient needs to have continuous cardiac monitoring and frequent
monitoring of vital signs and be premedicated for the TIL infusion. Patients can
have transient adverse effects such as chills, fever, shortness of breath, and tachycardia during and immediately following infusion (Radvanyi etal., 2012).
The rst dose of IL2 is administered IV within 24h of TIL infusion and repeated
every 8to 12h. The side effects of IL-2 are varied, and their management can be
counterintuitive. The Cytokine Working Group (CWG) recommends that centers
that are naïve to the administration of IL-2 perform the rst ten or so infusions in an
intensive care setting (Dutcher etal., 2014). The CWG and National Cancer Institute
have established best management practices for the infusion of high-dose IL-2
(Dutcher etal., 2014). Patients will need continuous cardiac monitoring, frequent
monitoring of vital signs, and assessment. The CWG recommends that nurses have
a low nurse-to-patient ratio to allow for frequent monitoring and management of
adverse effects of IL-2 (Dutcher etal., 2014). The most common side effects are due
to cytokine release syndrome and capillary leak syndrome (Dutcher etal., 2014;
Rohaan etal., 2022). Function of multiple organ systems can be affected. Frequently
patients develop signicant hypotension and extracellular uid overload which is
better managed with inotropic therapy rather than uid boluses. The patient should
be evaluated by a provider before each infusion to ensure safety. The peak adverse
effect of each dose occurs 4–6h after the infusion. The heart rate, pulse oximetry,
and blood pressure should reach or be near reaching baseline before the next infusion (Dutcher etal., 2014). If the patient needs to be moved to the intensive care
unit, the experienced oncology team needs to continue care over the patient. The
majority of adverse effects resolve before the patient is discharged from the hospital. Treatment-related adverse events are from lymphodepleting chemotherapy and
IL-2 and include thrombocytopenia, anemia (56%), febrile neutropenia (55%), neutropenia (39%), hypophosphatemia (35%), leukopenia (35%), and lymphopenia
(32%) (Sarnaik etal., 2021). No lileucel-related serious adverse events nor recurrence of immune-related adverse events from earlier immune checkpoint inhibitor
therapy were reported six months after therapy (Sarnaik etal., 2021).
In summary, TIL therapy is promising with manageable side effects and could be
an effective strategy against melanoma progressing on immune checkpoint therapies (Sarnaik etal., 2021; Rohaan etal., 2022). Further improvements in TIL technology are underway with its use tested in other solid tumors (Fig.4.1).
4 Tumor-Inltrating Lymphocyte (TIL) Therapy
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Fig. 4.1 Schematic of TIL therapy
37
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