1
The promise of neoadjuvant immunotherapy and surgery for cancer treatment 1
Jake S. O’Donnell1,2,3*
, Esmée P. Hoefsmit4*
, Mark J. Smyth1,3
, Christian U. Blank4,5,#
, 2
Michele W.L. Teng1,3,#
3
4
1Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical 5
Research Institute, Herston 4006, Queensland, Australia. 6
2Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research 7
Institute, Herston 4006, Queensland, Australia. 8
3School of Medicine, The University of Queensland, Herston 4006, Queensland, Australia. 9
4Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, 10
Amsterdam, The Netherlands 11
5Medical Oncology Department, Netherlands Cancer Institute, Amsterdam, The 12
Netherlands 13
14
*Contributed equally to this work 15
#Co-senior authors 16
Corresponding Author: M.W.L. Teng 17
QIMR Berghofer Medical Research Institute 18
300 Herston Road, Herston 4006, Queensland, Australia. 19
Phone number +61 7 3845 3957 20
22
Running title: Neoadjuvant immunotherapy for the treatment of cancers 23
24
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mailto:michelehttp://clincancerres.aacrjournals.org/
2
Conflict of Interest: 26
JSO has no conflict of interest 27
EPH has no conflict of interest 28
M.J.S is funded by research agreements from Bristol Myers Squib and Tizona Therapeutics 29
and has an advisory board role for Tizona Therapeutics and Compass Therapeutics . 30
CUB reports advisory roles for BMS, MSD, Roche, Novartis, Pfizer, GSK, Lilly, GenMab, 31
Pierre Fabre and grant support by BMS, Novartis, and NanoString. 32
MWLT has no conflict of interest 33
34
Funding: M.J.S. is funded by a National Health and Medical Research Council of Australia 35
(NH&MRC) Senior Principal Research Fellowship (1078671) and NH&MRC Program Grant 36
(1132519). M.W.L.T. is supported by a NH&MRC Career Development Fellowship 37
(1159655) and Project Grant (1098960). J.S.O’D. was supported by an Australian Post-38
Graduate Award and QIMR Berghofer PhD Top-Up Scholarship. 39
40
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Abstract 43
Cancer immunotherapies utilizing immune checkpoint inhibitors (ICIs) have demonstrated 44
durable efficacy in a proportion of patients with advanced/metastatic cancers. More recently, 45
the use of ICIs for the adjuvant treatment of patients with surgically resectable melanoma 46
have also demonstrated efficacy by improving relapse-free survival and in the case of 47
ipilimumab (anti-CTLA-4) also improving overall survival. While promising, the effective 48
scheduling of surgery and immunotherapy and its duration is not well elucidated. Recent 49
preclinical studies suggest that surgery followed by adjuvant therapy might be suboptimal as 50
compared to an approach in which immunotherapy is applied before surgery (neoadjuvant 51
immunotherapy). Encouraging findings from early phase clinical trials in melanoma, NSCLC 52
and glioblastoma support the idea that neoadjuvant immunotherapy might have improved 53
clinical efficacy over an adjuvant application. In this review we discuss the existing rationale 54
for the use of neoadjuvant immunotherapy, its apparent strengths, weaknesses, and 55
implications for the design of future clinical trials. 56
57
Key Words: Neoadjuvant, Immunotherapy, Cancer, Adjuvant, Surgery, Metastases, Minimal 58
Residue Disease, Scheduling 59
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Introduction 68
Cancer immunotherapies using antibodies targeting CTLA-4 and PD-1/PD-L1 relieve tumor-69
induced immune suppression and induce durable tumor regression (1). When used alone or in 70
combination, these immune checkpoint inhibitors (ICIs) have demonstrated remarkable 71
therapeutic efficacy in a proportion of patients with advanced/metastatic cancers such as 72
melanoma, Hodgkin Lymphoma, Merkel cell carcinoma, renal cell carcinoma, bladder 73
cancer, MSI (micro-satellite instability) high tumors, and non-small cell lung carcinoma 74
(NSCLC) among others (1). In an effort to increase the proportion of patients who durably 75
respond to these therapies, focus is now being placed on how immunotherapies can be 76
optimally incoprorated with mainstay oncological/medical practices such as cancer surgery, 77
radiotherapy, and chemotherapy. Despite the successes of systemic therapies so far, cancer 78
surgery remains the most effective therapeutic strategy for resectable disease (2). Among 79
patients who undergo complete primary tumor resection at high risk of relapse, adjuvant 80
therapies are often administered with the aim of eliminating microscopic or minimal residual 81
disease and thus preventing relapse (Fig. 1A). Recent studies have demonstrated that the use 82
of adjuvant anti-CTLA4 or anti-PD-1 post-surgery improved recurrence-free survival (RFS) 83
and overall survival (OS) in melanoma patients that were at high risk of relapse (3-5). 84
85
In contrast to adjuvant therapy, neoadjuvant (pre-operative) therapy (Fig. 1B) using 86
chemotherapy and radiotherapy has demonstrated specific advantages, particularly in breast 87
(6, 7), bladder (8), laryngeal (9), esophageal (10), and rectal cancers (11). This includes 88
allowing one to: (i) determine on-treatment therapeutic response of an individual patient; (ii) 89
to reduce tumor burden prior to surgery; and (iii) to use pathological response data as a 90
surrogate biomarker for RFS and OS (12, 13). Neoadjuvant approaches in ICI are rare so far. 91
However, in the context of cancer immunotherapy, neoadjuvant treatment may offer an 92
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additional advantage; immunotherapies enhance T cell activation the moment antigen is 93
encountered (14). Exposure to antigen during the period in which the major tumor mass is 94
present may increase the breadth and durability of tumor-specific T cell responses. 95
Throughout this review we will discuss the existing and emerging data related to the use of 96
cancer immunotherapies in the neoadjuvant setting, the mechanisms responsible for the 97
efficacy of this schedule, clinical findings, highlight potential caveats, and unanswered 98
questions. 99
100
Evidence for why neoadjuvant may be more effective than adjuvant immunotherapies 101
Supporting pre-clinicial studies 102
Recent preclinical mouse studies have demonstrated that neoadjuvant immunotherapy 103
improved long-term survival and enhanced anti-tumor immune responses compared with the 104
same therapy administered in the adjuvant setting (15). This was first shown using two mouse 105
models of spontaneously metastatic triple negative breast cancer (TNBC) in which various 106
combination immunotherapies were administered in either a neoadjuvant or adjuvant setting 107
before or after primary tumor resection, respectively (15). Regardless of the types of 108
immunotherapy used, including anti-CD25 to deplete regulatory T cells (Tregs), or anti-PD-1 109
alone or in combination with agonistic anti-CD137 to activate effector T and natural killer 110
(NK) cells, neoadjuvant treatment was superior to adjuvant treatment in the eradication of 111
lethal micrometastases, resulting in cures in a significant proportion of treated mice (15). 112
Subsequently, other groups have tested the efficacy of other neoadjuvant immunotherapy 113
combinations in different pre-clinical mouse models. In mouse models of TNBC, one study 114
demonstrated that the combination of neoadjuvant poly(I:C)(to stimulate type I IFN) and anti-115
PD-1 prolonged survival (16), while in another study, neoadjuvant oncolytic virotherapy 116
before surgery sensitized TNBC to immune checkpoint therapy resulting in cures in a 117
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proportion of treated mice (17). In a transgenic mouse model of resectable pancreatic ductal 118
adenocarcinoma (PDAC), a treatment regime of neoadjuvant combination anti-PD-1 and 119
gemcitabine followed by adjuvant anti-CD96 and gemcitabine impressively cured a 120
proportion of mice (18). Interestingly, the addition of adjuvant anti-CD96 (a NK and T cell 121
checkpoint regulated by interactions with CD155 on tumor and myeloid cells) to the 122
treatment was critical for the generation of long-term survivors as treatment with anti-PD-1 123
and gemcitabine alone only prolonged survival. While some of the immunotherapies used in 124
these pre-clinical studies are currently still in the early-stage of clinical development, overall 125
these studies illustrate the concept that therapies that target the immune system to relieve 126
tumor-induced immune suppression and/or to activate anti-tumor immunity may be more 127
effective when given in a neoadjuvant context. In contrast, chemotherapies such as paclitaxel 128
which does not depend on host immunity for its efficacy did not confer improved benefit 129
when given as a neoadjuvant (15). As such, these encouraging pre-clincial findings provided 130
strong impetus for the clinical assessment of neoadjuvant immunotherapy. 131
132
Supporting clinical studies 133
To date, two small clinical trials have directly compared neoadjuvant and adjuvant ICIs either 134
alone or in combination in melanoma and glioblastoma. In the first clinical trial that 135
performed a head-to-head comparison of adjuvant and neoadjuvant ICIs for the treatment of 136
stage III resectable melanoma, two doses of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) 137
were administered concurrently at three-week intervals followed by surgery at six weeks 138
(NCT02437279). Additional treatments were administered following surgery in both groups; 139
however, treatment-related toxicities were dose-limiting resulting in a median of two doses 140
given (range 1-4 courses)(13). In these patients, RFS and OS was 80% and 90% respectively 141
for patients treated with neoadjuvant ICI therapy and 60% and 67% respectively for patients 142
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treated with adjuvant ICI therapy at a median follow-up time of 32 months (19). 143
While the melanoma study by Blank et al., was not powered to compare clinical outcome 144
parameters after neoadjuvant versus adjuvant therapy, its findings were supported by a 145
similarly high response rates of neoadjuvant ipilimumab plus nivolumab in anothermelanoma 146
study by Amaria et al where ipilimumab (3 mg/kg) plus nivolumab (3 mg/kg) were given 147
every three weeks with surgery at week nine (NCT02519322). The PFS and OS for treatment 148
with ipilimumab plus nivolumab was 82% (at 17.2 months) and 100% (at 24.4 months) 149
respectively versus 58% and 76% (both at 22.6 months) respectively for treatement with 150
nivolumab (20). In the 2nd
study comparing neoadjuvant and adjuvant immunotherapy, 151
patients with glioblastoma were randomised to receive either neoadjuvant (including follow-152
up adjuvant) or adjuvant pembrolizumab (21). Patients in the neoadjuvant arm were treated 153
once with pembrolizumab (200 mg) 14±5 days before surgical resection; patients in the 154
adjuvant only arm did not. Both groups received pembrolizumab (200 mg) every 3 weeks 155
following surgery. The neoadjuvant treatment schedule was found to significantly increase 156
median PFS (3.3 months vs 2.4 months) and median ORR (13.7 months vs 7.5 months). In a 157
second study of glioblastoma, nivolumab (3 mg/kg) 14±3 days before surgery, and continued 158
every 2 weeks following surgery was found to result in unexpectedly high PFS (4.1 months) 159
and ORR (7.3 months) (22). 160
161
Clinically, the efficacy of single arm neoadjuvant immunotherapy in melanoma, NSCLC and 162
glioblastoma have also been reported. In the Amaria study, anti-PD-1 neoadjuvant 163
monotherapy was also evaluated (20). Melanoma patients were treated with neoadjuvant 164
nivolumab (3 mg/kg) every two weeks with surgery at week eight, followed by further 165
adjuvant treatment for 6 months (20). In another neoadjuvant study in melanoma, one course 166
of neoadjuvant pembrolizumab followed by surgery at week three followed by adjuvant 167
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treatment for a year was reported (63% RFS and 93% at 2 years) (23). While treatment-168
related toxicities were clearly reduced by administering only anti-PD-1, this was at a cost of 169
significantly lower response rates (pCR 25% (20) and 30% (23)). In contrast, pCR differed in 170
two small studies of early stage NSCLC. In the first, two doses of nivolumab (3 mg/kg) were 171
administered every two weeks, with surgery at week four resulted in pCR of 45% (73% RFS 172
at 18 months) (24) and in the second study, two doses of atezolizumab (1200 mg) every 3 173
weeks, with surgery at week 6 had pCR of 21% (25). Going forward, new trials with larger 174
cohorts of patients will inform on the true response rate. In a study of glioblastoma patients, 175
neoadjuvant nivolumab was given to patients who required salvage surgery to treat relapsed 176
disease or new diagnosed patients who required surgery (22). Although no obvious clinical 177
benefit was reported for salvage surgery patients, two of the three new diagnosed patients 178
remain alive 34 and 28 months later. Overall, these studies suggest that neoadjuvant ICI 179
might be more effective than the more traditional adjuvant schedule. 180
181
Immune determinants of effective neoadjuvant immunotherapy 182
The mechanistic basis underpinning the improved efficacy of neoadjuvant over adjuvant 183
immunotherapy in pre-clinical mouse models, and in the limited published clinical trials, is 184
not fully understood. A widely accepted hypothesis is that the presence of the full tumor mass 185
at the start of immunotherapy allows the induction of a broader and stronger T cell response 186
(13). Another idea might be that the presence of activated tumor-specific T cells before 187
surgery might prevent metastatic spreading. Preclinical and translational data support the first 188
idea: effective neoadjuvant immunotherapy was associated with rapid expansion of tumor-189
specific CD8+ T cells in the peripheral blood (Fig. 2) (15). This was first shown in mice, in 190
which the greatest increases in the proportion of peripheral blood tumor-specific CD8+ T 191
cells was associated with long-term survival (15). Recently, this has also been found in 192
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humans; CD8+ T cell clones identified in the primary tumor on-treatment expanded in the 193
blood relative to pre-treatment levels, associated with improved RFS (13, 20, 24). In addition, 194
in some cases following neoadjuvant immunotherapy, peripheral expansion of T cell clones 195
not detected in the primary tumor on-treatment was also observed (13, 20, 24). This has two 196
possible explanations: (i) that the expanded T-cell clones were already present in the primary 197
tumor, but baseline readouts fell below the limit of detection (13); or (ii) that the proliferative 198
burst observed for immunodominant T cell clones immediately following treatment promoted 199
epitope spreading by enabling iterative revolutions of the cancer immunity cycle and the 200
generation of new tumor-specific CD8+ T cells (Fig. 2)(26). These explanations are not 201
mutually exclusive. The expansion of sub-dominant clones appears to be important for the 202
efficacy of cancer immunotherapy. Indeed, these cells are potentially less susceptible to the 203
development of a dysfunctional phenotype than the immunodominant T cell population, and 204
thus may play an important role in the ongoing anti-tumor immune response (27). This 205
hypothesis has been born-out to some extent with the finding that all melanoma patients who 206
relapsed following neoadjuvant ICI demonstrated inferior expansion of sub-dominant T cell 207
clones on therapy (13). 208
209
In mice, we recently found that cross-presenting Batf3+ DCs in the primary tumor and dLN as 210
well as type I interferons (IFNs) were essential for the systemic expansion of tumor-specific 211
CD8+ T cells following neoadjuvant immunotherapy (28). This was corroborated by the 212
demonstration in human melanomas that a BATF3 gene signature, T cell inflamammatory 213
signature, and a T cell signature were associated with an improved outcome after neoadjuvant 214
immunotherapy (13, 28). Cross-presenting DCs are essential for the priming and activation of 215
naïve T cells (29) and shown both in pre-clinical models and clinically to play an important 216
role in the reinvigoration of dysfunctional CD8+ T cell clones in the tumor following PD-217
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1/PD-L1 blockade (30-32). The efficacy of anti-PD-1 therapy has also beeen shown to be 218
dependent on CD28 signaling in T cells, initiated by interactions with CD80 and CD86 219
expressed by APCs (33). While speculative, the presentation of antigen to dysfunctional 220
CD8+ T cells by antigen-presenting cells in the tumor and/or dLN might be necessary for 221
their functional re-invigoration, and may enable de novo T cell priming against novel 222
epitopes (33) released by tumor cells killed by pre-existing tumor specific T cells following 223
re-invigoration. 224
225
It is important to note that pre-clinically, some peripheral CD8+ T cell expansion was 226
observed following adjuvant immunotherapy; however the magnitude of this expansion was 227
considerably smaller than that which occurred following neoadjuvant treatment (15). One 228
explanation is that the primary tumor itself plays a critical role in facilitating tumor-specific T 229
cell expansion/priming to occur at the time of treatment. The presence or absence of the 230
primary tumor at the time of treatment was the only salient difference between the 231
neoadjuvant and adjuvant schedules, respectively. Also, the primary tumor is likely to be the 232
main source of tumor antigen and to be enriched for T cells with tumor specificity (34). 233
Presumably, the expansion that occurs following treatment might take place at sites of 234
metastases; however the lack of response observed to this treatment protocol might be due to 235
an inadequate T cell to tumor antigen ratio (35), the absence of a T cell response against 236
antigen expressed by tumor cells in metastases, or that metastasis-infiltrating T cells are 237
unable to be reinvigorated by therapy (36). In the two trials that compared neoadjuvant and 238
adjuvant immunotherapies in melanoma (13) and glioma (21), both studies reported an 239
increased expansion of TCR clones in the blood of these patients treated with neoadjuvant 240
compared to adjuvant immunotherapy. These two studies provide preliminary evidence that 241
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neoadjuvant compared to adjuvant immunotherapy may better expand T cells although this 242
will need to be confirmed in more clinical trials. 243
244
Timing of surgery and neoadjuvant immunotherapy 245
Pre-clinically, the presence of the primay tumor at the time of treatment appears to be 246
important for the efficacy of neoadjuvant immunotherapy (15), However, this effect depends 247
on the timing of tumor resection relative to treatment (Liu et al., Oncoimmunology, in press). 248
Pre-clinical assessment of neoadjuvant immunotherapy in mice involved administration of 249
two doses of antibody therapy followed by surgery; each event separated by two days. It has 250
recently been shown that varying this schedule by either delaying or shortening the time to 251
surgery following neoadjuvant treatment dramatically impacted overall survival (Liu et al., 252
Oncoimmunology, in press). Specific comparisons drawn between tumor-specific CD8+ T 253
cells from mice receiving a short neoadjuvant treatment schedule (treatments completed 2 254
days before surgery), and those in which surgery was delayed (treatments completed 8 days 255
before surgery) showed reduced cytokine production and abundance within metastatic sites. 256
This suggests that increasing the duration of exposure to bulk tumor antigen following 257
neoadjuvant treatment may result in re-invigorated T cells to re-enter into a dysfunctional 258
state. To date, neoadjuvant ICIs trials have used different schedules (Table 1). While the 259
Amaria and Huang study of neoadjuvant anti-PD-1 in early stage melanoma gave similar 260
pCR of 25 and 30% respectively, interestingly, the trial in the Amaria study was stopped 261
early on the basis of an early observation of disease progression, preventing surgical resection 262
(20). In contrast, all patients successfully underwent complete resection in the Huang study. 263
The main difference between these studies was the longer duration between treatment courses 264
and surgery. 265
266
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Translationally, determining the optimal treatment and surgery schedule for neoadjuvant 267
treatment of humans is likely to be challenging. Before determining the optimal duration of 268
treatment and surgery, it will be important to understand at what point T cell re-expansion 269
and effector function are optimal, and at what point retention of the macroscopic tumor 270
negatively affects these parameters. Experimentally, this is likely to be extremely 271
challenging, however, it was recently shown that measuring antigen-specific T cell responses 272
in humans over time was possible with systemic deuterium labelling (37). Currently the 273
international neoadjuvant melanoma consortium (INMC) advises for practical reasons 274
(comparability of the individual studies and prevention of deterioration of non-responders) a 275
neoadjuvant timeframe of 6-8 weeks before surgery (Amaria et al., manuscript in 276
preparation). 277
278
T cell memory 279
An interesting observation made in mouse models following neoadjuvant-immunotherapy has 280
been the persistence of tumor-specific CD8+ T cells in the blood of tumor-free mice at 281
detectable frequency throughout life (Fig. 2) (15). Whether this maintenance of a tumor-282
specific T cell population contributes to the efficacy of the anti-tumor immune response 283
itself, or is simply a consequence of an effective response is not clear. However, this is likely 284
to be a positive outcome of effective neoadjuvant immunotherapy; providing life-long 285
protection against tumor re-emergence (38). Clinically, a case study reported the ability to 286
identify and track the long-term persistence of mutant oncogene specific T cells in two 287
patients with advanced NSCLC and CRC who derived long-term clinical benefit from PD-1 288
blockade (39). It will be of interest to see whether this effect is observed among human 289
patients who demonstrate a complete response to neoadjuvant immunotherapy. 290
Evaluation of neoadjuvant immunotherapies across different cancer types 291
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The recent success of neoadjuvant ICIs in the treatment of early stage resectable cancers in 292
melanoma, NSCLC, and glioblastoma has led to enthusiasm to evaluate different neoadjuvant 293
ICI treatment strategies across different solid cancer types. An overview on neoadjuvant ICI 294
trials prior to surgery across different tumor types that are active, or recruiting are shown in 295
Table 1 (compiled from clinicaltrial.gov). Most clinical studies (phase I, II or III) are 296
ongoing in NSCLC, head and neck and urologic cancers, using different schemes and drug 297
combinations of PD-1, PD-L1 or CTLA-4 blocking antibodies. In addition, various clinical 298
trials are underway in melanoma, breast cancer, ovarian cancer, gastroesophageal cancers, 299
colorectal cancer, hepatocellular carcinoma, pancreatic cancer and sarcoma, combining 300
different ICIs, and in some cases combining ICI with conventional therapies such as 301
chemotherapy, endocrine therapy, targeted therapy, or radiotherapy. Whether these clinical 302
trials result in long-term, durable prevention of relapse and early read-outs like pCR rate, 303
needs to be confirmed to speed up testing different combinations. Moreover, it needs to be 304
established which patients benefit from ICI monotherapies, and under which circumstances 305
combination ICIs are preferable. This is important given the variety of immune-related 306
druggable targets currently being tested (e.g. LAG-3, VISTA, BTLA, TIM-3, OX-40, CD28, 307
CD137, GITR, TIGIT). The design of neoadjuvant trials (including a streamlined material 308
collection) should be structured to enable comparability across trials. To date, only one such 309
initiative in melanoma, the INMC, exists with this aim. 310
311
While neoadjuvant immunotherapy emerges to be promising, ICI-induced immune related 312
adverse events (irAEs), particularly those used in combinations might interfere with 313
potentially curative surgery. These irAEs are managed with immune modulating drugs, such 314
as corticosteroids, and in some cases infliximab or other immunosuppressive therapies (40). 315
In the trials published to date, irAEs induced by neoadjuvant ICIs did not delay the 316
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preplanned surgery time point; demonstrating that neoadjuvant therapy is feasible. In the 317
follow up trial to OpACIN, adjusting the combination scheme (ipilimumab 1 mg/kg plus 318
nivolumab 3 mg/kg) and applying a maximum of two treatment courses reduced the rate of 319
grade 3/4 toxicities to 20%, while preserving therapeutic efficacy (77% pRR with 57% pCR 320
rate) (41). Whether the use of immunosuppressive therapies for the management of irAEs 321
hampers long-term RFS is not known yet. Our own restricted experience argues against this 322
concern (19). 323
324
Monitoring response to neoadjuvant immunotherapy 325
A comprehensive understanding of the efficacy and safety of neoadjuvant therapy is essential 326
to guide treatment. In this regard, having standardized strategies to determine response in 327
patients is of high importance. Clinical evaluation of therapy effectiveness as change in tumor 328
burden is assessed by either radiology following the WHO criteria (42), or Response 329
Evaluation Criteria in Solid Tumors (RECIST) (43, 44). However, in neoadjuvant 330
immunotherapy, assessing tumor response according to conventional response criteria may 331
underestimate the pathologic response, which is to date the best predictor of RFS (13, 20). 332
Therefore, standardized guidelines for pathological assessment of resection specimens after 333
neoadjuvant therapy to grade pathologic responses are crucial. Rationally, these might 334
include criteria such as immune-related pathological features including immune infiltrate 335
(lymphocytes, plasma cells, lymphoid aggregates and macrophages) together with wound 336
healing characteristics (immature, proliferative fibrosis and neovascularization) (45). To 337
further advance assessment and prediction of responses in patients receiving neoadjuvant 338
immunotherapy, robust biomarkers are required. Results from the first clinical trials 339
employing neoadjuvant ICIs in patients with melanoma identified markers that associated 340
with response. A study with patients with macroscopic stage III melanoma receiving 341
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neoadjuvant ipilimumab plus nivolumab identified that the expansion of tumor-resident T cell 342
clones and a favorable IFN- gene signature were associated with RFS (13). Another study in 343
patients with resectable stage III or oligometastatic melanoma receiving neoadjuvant 344
combined ipilimumab plus nivolumab or nivolumab alone showed that patients whose tumors 345
displayed greater CD8+ T cell infiltration, of which TCR clonality was higher, were more 346
likely demonstrate a positive response to therapy (20). In a prospective study of 27 patients 347
with either resectable stage III, or oligometastatic melanoma treated with neoadjuvant 348
pembrolizumab showed patients with brisk lymphocyte infiltration into the tumor had a 349
higher RFS (89%) compared to patients with lower lymphocyte infiltration (27%) (23). Early 350
results in colon cancer, combining ipilimumab and nivolumab-treatment before surgery, 351
showed major pathological responses (
16
tumor DNA (ctDNA) can also be measured. A study in patients with stage III melanoma 367
reported that pre-operative ctDNA predicted melanoma specific survival independent of 368
AJCC stage (47). Potentially, changes in ctDNA pre- and post- neoadjuvant immunotherapy 369
may be another biomarker of response. 370
371
Therapy efficacy and treatment-induced irAEs are strongly independent in neoadjuvant 372
immunotherapy (Rozeman et al., under revision), therefore it would be advantageous to 373
identify patients upfront that are most likely to respond to treatment and/or have a high 374
chance to develop severe irAEs. This is especially important for neoadjuvant approaches in 375
stage III disease, since in melanoma up to 50% of these patients can be cured by surgery 376
only, and thus do not need any adjuvant therapies (48). Given the high incidence of irAEs 377
induced upon ICI, particularly in combination approaches (49), it is crucial to identify 378
biomarkers that can predict response and development of treatment-induced (irreversible) 379
severe irAEs. Going forward, identification of biomarkers that reflect the complex tumor-380
immune system interaction, and immune system-host interaction will aid clinicians decide the 381
patients that will benefit most from neoadjuvant immunotherapy. 382
383
Unanswered questions 384
There are currently many questions that remain unanswered with regard to the use of 385
neoadjuvant cancer immunotherapy. A key question is to demonstrate the improved efficacy 386
of neoadjuvant over adjuvant immunotherapy in randomized phase III clinical trials. Other 387
questions include, (i) will neoadjuvant immunotherapy be effective for all tumor types? The 388
existing literature suggests that in order for an effective response to occur following 389
neoadjuvant treatment, an ongoing, albeit dysfunctional immune response, must be present 390
within the primary tumor before treatment. Therefore it is unlikely that a tumor in which a T 391
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cell response has not been generated, or one in which tumor-specific T cells are excluded 392
from tumor tissue would respond any better to neoadjuvant immunotherapy than adjuvant 393
immunotherapy. However, this is yet to be directly tested. (ii) What role does surgery play, 394
and will other tumor ablation therapies work as effectively? For example, if radiotherapy or 395
chemotherapy are capable of destroying the macroscopic tumor, would the neoadjuvant 396
immunotherapy effect hold? Some chemotherapy and radiotherapy has been shown to 397
promote immunogenic cell death; capable of kick-starting an anti-tumor immune response 398
(50). It is possible that non-surgical intervention could be beneficial, given the finding that 399
the immune suppression associated with surgical wound repair can enable the revival and 400
dissemination of occult metastases (51). Additionally, it is not known whether chemotherapy 401
and radiotherapy might be more effective in combination with neoadjuvant as opposed to 402
adjuvant immunotherapy. (iii) Are particular immunotherapies more effective than others in a 403
neoadjuvant context? To date, it seems that combination of anti-PD1 and anti-CTLA4 is 404
superior to monotherapy anti-PD1 in terms of pCR, however this does appear to come at the 405
cost of increased irAEs. (iv) Finally, what are the determinants of response for neoadjuvant 406
immunotherapy? Understanding why neoadjuvant immunotherapy is effective for some 407
patients but not others may allow the identification of biomarkers of response and 408
mechanisms of resistance as recently reported by Huang et al (23). Should future clinical 409
trials validate the promising data from current neoadjuvant immunotherapy clinical trials, this 410
approach may become standard of care for the treatment of patients with early stage cancer 411
that are at high risk of relapse. 412
413
414
415
416
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417
418
419
420
421
Figure Legends 422
Figure 1. Neoadjuvant versus adjuvant immunotherapy treatment schedule 423
A. An adjuvant treatment schedule involves identification of a primary tumor, its resection, 424
followed by administration of cancer immunotherapies. This option allows for rapid surgical 425
intervention and adjuvant therapies are administered with the aim of combatting microscopic 426
metastatic disease. Treatment is often continuous, lasting for years at a time if immune-427
related adverse events are absent or manageable. Dynamic biomarkers are limited in this 428
setting to pre-treatment tumor and analysis of blood. B. A neoadjuvant treatment schedule 429
involves identification of a primary tumor, followed by administration of cancer 430
immunotherapies. To date, two to three doses have been provided prior to surgery with a time 431
to surgery from treatment from 4 to 9 weeks. Continuous administration of immunotherapy 432
following surgery is an option, however, immune-related toxicities are common. This 433
treatment schedule enables comparisons to be drawn between pre- and on-treatment primary 434
tumor specimens including pathological response, immune cell infiltration and T cell 435
profiling which can be used to identify tumor-specific T cells within the periphery following 436
treatment. 437
438
Figure 2. Neoadjuvant immunotherapy and the tumor-specific T cell response 439
A. Following administration of cancer immunotherapy, re-invigorated tumor-specific CD8+ 440
T cells can undergo re-expansion. These T cells can kill existing tumor and re-circulate into 441
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the blood. In addition to this, the existing tumor-specific T cell response can result in the 442
release of new tumor antigens that are presentated by antigen presenting cells (APCs) to 443
prime naïve T cells with tumor specificity against distinct tumor where they circulate in the 444
blood to the tumor/metastatic sites. B. Following primary tumor resection, the remaining 445
circulating tumor-specific CD8+ T cells, and those present at metastatic sites have an 446
increased T cell:tumor ratio, which is likely to provide an advantage in the destruction of 447
remaining tumor tissue. C. Following clearance of tumor antigen, a stable pool of tumor-448
specific CD8+ T cells can remain. It is not clear whether these are essential for the 449
maintenance of a complete response, however, they have been observed to remain for life 450
within long-term surviving pre-clinical mouse models. 451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
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467
468
469
470
471
472
References 473
474
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Table 1. Ongoing neoadjuvant immune checkpoint inhibitors trials prior to surgery across different tumor types
Clinical trial.gov identifier
Study name Phase of the clinical trial
Trial status Estimated enrollment
Non-Small Cell Lung Cancer
NCT03237377 Neoadjuvant Immunoradiation for Resectable Non-Small Cell Lung Cancer Phase II Recruiting 32
NCT03197467 Neoadjuvant Anti PD-1 Immunotherapy in Resectable Non-small Cell Lung Cancer (NEOMUN)
Phase II Recruiting 30
NCT03081689 Neo-Adjuvant Immunotherapy With Nivolumab for Non Small Cell Lung Cancer Patients Phase II Active, not recruiting
46
NCT02994576 Atezolizumab as Induction Therapy in Non-small Cell Lung Cancer (PRINCEPS) Phase II Recruiting 60
NCT02818920 Neoadjuvant Pembrolizumab (TOP 1501) Phase II Recruiting 32
NCT02259621 Neoadjuvant Nivolumab, or Nivolumab in Combination With Ipilimumab, in Resectable NSCLC (NA_00092076)
Phase II Recruiting 30
NCT02927301
A Study of Atezolizumab as Neoadjuvant and Adjuvant Therapy in Resectable Non-Small Cell Lung Cancer (NSCLC) - Lung Cancer Mutation Consortium (LCMC3)
Phase II Recruiting 180
NCT02572843 Anti-PD-L1 in Stage IIIA(N2) Non-small Cell Lung Cancer (NSCLC) Phase II Recruiting 68
NCT02716038 Neoadjuvant MPDL3280A, Nab-paclitaxel and Carboplatin (MAC) in NSCLC Phase II Recruiting 30
NCT03158129 Study Of Induction Checkpoint Blockade For Untreated Stage I-IIIA Non-Small Cell Lung Cancers Amenable For Surgical Resection
Phase II Recruiting 66
NCT03732664 Neoadjuvant Nivolumab in Resectable Non-Small-Cell Lung Cancer Phase I Recruiting 40
Head and Neck Cancer
NCT03700905 Study of Nivolumab Alone or in Combination With Ipilimumab as Immunotherapy vs Standard Follow-up in Surgical Resectable HNSCC After Adjuvant Therapy (IMSTAR-HN)
Phase III Recruiting 276
NCT02296684 Immunotherapy With MK-3475 in Surgically Resectable Head and Neck Squamous Cell Carcinoma
Phase II Recruiting 66
NCT03021993 Trial of Nivolumab as a Novel Neoadjuvant Pre-Surgical Therapy for Locally Advanced Oral Cavity Cancer
Phase II Recruiting 19
NCT03247712 Neoadjuvant Immunoradiotherapy in Head & Neck Cancer Phase I/II Recruiting 18
NCT03003637 ImmunoModulation by the Combination of Ipilimumab and Nivolumab Neoadjuvant to Surgery In Advanced or Recurrent Head and Neck Carcinoma (IMCISION)
Phase I/II Recruiting 32
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NCT03129061 Study to Evaluate Immunological Response to PD-1 Inhibition in Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Phase I Recruiting 24
NCT02812524 Ipilimumab for Head and Neck Cancer Patients Phase I Recruiting 18
Melanoma
NCT03639948 Neoadjuvant Combination Targeted and Immunotherapy for Patients With High-Risk Stage III Melanoma (NeoACTIVATE)
Phase II Recruiting 30
NCT02519322
Nivolumab With or Without Ipilimumab or Relatlimab Before Surgery in Treating Patients With Stage IIIB-IV Melanoma That Can Be Removed by Surgery
Phase II Recruiting 53
NCT02977052
Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo), PRADO extension cohort
Phase II Recruiting 110
NCT02858921
Neoadjuvant Dabrafenib, Trametinib and/or Pembrolizumab in BRAF Mutant Resectable Stage III Melanoma (NeoTrio)
Phase II Recruiting 60
NCT02306850 Neoadjuvant Pembrolizumab for Unresectable Stage III and Unresectable Stage IV Melanoma (NeoPembroMel)
Phase II Recruiting 15
Urologic malignancies
NCT03055013 Nivolumab in Treating Patients With Localized Kidney Cancer Undergoing Nephrectomy Phase III Recruiting 766
NCT03406650 Neoadjuvant and Adjuvant Durvalumab in Combination With Neoadjuvant Chemotherapy in Patients With Operable Urothelial Cancer. (SAKK 06/17)
Phase II Recruiting 61
NCT02845323 Neoadjuvant Nivolumab With and Without Urelumab in Patients With Cisplatin-Ineligible Muscle-Invasive Urothelial Carcinoma of the Bladder
Phase II Recruiting 22
NCT03234153 Neoadjuvant Immunotherapy With Durvalumab and Tremelimumab for Bladder Cancer Patients Ineligible for Cisplatin (NITIMIB)
Phase II Recruiting 68
NCT02736266 Neoadjuvant Pembrolizumab for Muscle-invasive Urothelial Bladder Carcinoma Phase II Recruiting 90
NCT03387761 Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy (NABUCCO) Phase I Recruiting 24
NCT02812420 Durvalumab and Tremelimumab in Treating Patients With Muscle-Invasive, High-Risk Urothelial Cancer That Cannot Be Treated With Cisplatin-Based Therapy Before Surgery
Phase I Recruiting 35
NCT02762006 Neoadjuvant MEDI 4736 +/- Tremelimumab in Locally Advanced Renal Cell Carcinoma Phase I Recruiting 45
NCT02575222 Study of Neoadjuvant Nivolumab in Patients With Non-metastatic Stage II-IV Clear Cell Renal Cell Carcinoma
Phase I Active, not recruiting
30
NCT02595918 Nivolumab in Treating Patients With High-Risk Non-Metastatic Kidney Cancer Phase I Recruiting 29
Breast cancer
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NCT03639948 Neoadjuvant Phase II Study of Pembrolizumab And Carboplatin Plus Docetaxel in Triple Negative Breast Cancer (NeoPACT)
Phase II Recruiting 100
NCT02957968 Neoadjuvant Pembrolizumab + Decitabine Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca
Phase II Recruiting 50
NCT02997995 Durvalumab and Endocrine Therapy in ER+/Her2- Breast Cancer After CD8+ Infiltration Effective Immune-Attractant Exposure (ULTIMATE)
Phase II Recruiting 240
NCT02489448 Neoadjuvant MEDI4736 Concomitant With Weekly Nab-paclitaxel and Dose-dense AC for Stage I-III Triple Negative Breast Cancer
Phase I/II Recruiting 61
NCT02999477 A Study Of Changes In PD-L1 Expression During Preoperative Treatment With Nab-Paclitaxel And Pembrolizumab In Hormone Receptor-Positive Breast Cancer
Phase I Recruiting 50
NCT02833233 A Study of Pre-Operative Treatment With Cryoablation and Immune Therapy in Early Stage Breast Cancer
Phase I Active, not recruiting
5
Ovarian cancer
NCT03249142 Immunotherapy With Neo-adjuvant Chemotherapy for OVarian Cancer (INeOV) Phase I/II Recruiting 66
Gastroesophageal cancers
NCT03448835 Neoadjuvant Capecitabine, Oxaliplatin, Docetaxel and Atezolizumab in Resectable Gastric and GE-junction Cancer (PANDA)
Phase II Recruiting 20
NCT02918162 Perioperative Chemo and Pembrolizumab in Gastric Cancer Phase II Recruiting 40
NCT02735239 Study of Anti-PD-L1 in Combination With Chemo(Radio)Therapy for Oesophageal Cancer Phase I/II Recruiting 75
NCT03044613 Nivolumab +/- Relatlimab Prior to Chemoradiation Plus Nivolumab +/- Relatlimab With II/III Gastro/Esophageal Cancer
Phase I Recruiting 32
Colorectal cancer
NCT03026140 Nivolumab, Ipilimumab and COX2-inhibition in Early Stage Colon Cancer: an Unbiased Approach for Signals of Sensitivity (NICHE)
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© 2019 American Association for Cancer Research
Figure 1:
A. Adjuvant schedule
Primary tumor
Microscopicmetastases
Surgery Adjuvant therapy
Primary tumor
Microscopicmetastases
Neoadjuvant therapy Surgery
…
B. Neoadjuvant schedule
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© 2019 American Association for Cancer Research
Figure 2:
Re-expansion andrecirculation of
existing tumor-specificT-cell clones
Release of tumorantigens and re-entry
into thecancer immunity
cycle
1
23
4
5
6
7
Priming and activation
Trafficking into bloodand peripheral tissues
Infiltrationinto tumors
Recognition oftumor
cells by T cells
Death of tumor cells andrelease of tumor antigens
Release of tumorcell antigens
Primary tumor surgery
Functional circulatingCD8+ T cells
(metastases control)
Memorydifferentiation
Distal metastases present Complete responsePatient with resectableprimary tumor
Re-expansion and/or priming Contraction/maintenance
Memory
Systemicexpansion of T
cells with tumorspecificity
Immunotherapy
Tumor ordLN
A B C
Tumor antigenpresentation
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Published OnlineFirst April 30, 2019.Clin Cancer Res Jake S O'Donnell, Esmee P. Hoefsmit, Mark J. Smyth, et al. cancer treatmentThe promise of neoadjuvant immunotherapy and surgery for
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