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  • Case report
  • Open Access

Acquired resistance to immunotherapy in MMR-D pancreatic cancer

Journal for ImmunoTherapy of Cancer20186:127

https://doi.org/10.1186/s40425-018-0448-1

  • Received: 5 September 2018
  • Accepted: 8 November 2018
  • Published:

Abstract

Background

MMR-D pancreatic cancer have been reported to respond to checkpoint inhibitor therapy. Here, we report the first case of acquired resistance to immunotherapy in MMR-D pancreatic cancer.

Case presentation

A 45-year-old woman with unresectable MMR-D pancreatic cancer was initially treated with FOLFIRINOX, FOLFIRI, and stereotactic body radiation with stable disease burden. After 3 months, imaging showed progression of disease with an increase in CA19-9. She was subsequently enrolled in a clinical trial of an anti-PD-L1 antibody in combination with an IDO1 inhibitor. She demonstrated a partial response to therapy by RECIST 1.1 criteria with declining tumor markers. Twenty-two months after beginning immunotherapy, imaging revealed an increasing left ovarian cystic mass. There were no other sites of progressive disease. The patient underwent a total hysterectomy and bilateral salpingo-oophorectomy, appendectomy, omentectomy and pelvic lymphadenopathy. Pathology was consistent with a metastasis from the pancreas involving the endometrium and left ovary. Thereafter, the patient continued with PD-1 blockade therapy off protocol with no further progressive disease. Immune profiling showed high levels of CD8+ T cells and PD-1 positive immune cells infiltrating the tumor, with a moderate level of PD-L1 expression in both the immune cells and the tumor cells. Next generation sequencing found only the KRAS G12D and RNF43 G659Vfs*41 mutations were retained from the pre-treatment tumor in the treatment-resistant tumor.

Conclusions

This is the first report describing acquired resistance to immunotherapy in MMR-D pancreatic cancer with accompanying genomic and immune profiling. This case of oligoprogression in the setting of immunotherapy demonstrates the feasibility of localized treatment followed by continuation of immunotherapy to sustain ongoing response.

Keywords

  • Pancreatic cancer
  • Acquired resistance
  • Immunotherapy
  • Mismatch repair deficiency

Background

As checkpoint inhibitors have now entered broad use for the treatment of solid tumors, an increasing number of patients who initially respond to immunotherapy have been identified to develop acquired resistance. Such reports have been described in individuals with melanoma, non-small cell lung cancer (NSCLC), uterine leiomyosarcoma, and mismatch repair deficient (MMR-D) colorectal cancer (CRC) patients [17].

Pancreatic ductal adenocarcinoma (PDAC) has been largely refractory to single and combination checkpoint inhibitor therapy [810]. The tumor microenvironment of PDAC have been described to be largely immunosuppressive, with involvement of regulatory T cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressive cells (MDSCs) [1113]. Another contributing factor to PDAC’s immunotherapy resistance may be PDAC’s relatively low tumor mutation burden (TMB) and poor antigenicity, leading to impaired endogenous T cell response to the tumor [14]. TMB, in general, has been reported to have a significant correlation with objective response rate to PD-1 inhibition [15]. However, a rare subset of PDAC patients with MMR-D has been reported to have partial and complete responses to immunotherapy [1, 14]. MMR-D occurs at a frequency of < 1% of all PDAC patients and is typically associated with germline mutations in MMR genes, IHC loss of MMR expression, an elevated MSIsensor score, significantly prolonged survival times, and high TMB.

Here, we describe a patient with locally advanced MMR-D PDAC who had a partial response to checkpoint inhibitor therapy, but subsequently acquired resistance to therapy and developed a metastasis to the ovary. We evaluated tumor cell-intrinsic and extrinsic causes of acquired resistance in the metastatic tumor. We determined the tumor mutational profile before and after acquired resistance using next generation sequencing (NGS) and assessed PD-1, PD-L1, and CD8+ T cell levels in the immunotherapy-resistant tumor specimen.

Case presentation

Clinical course

An otherwise healthy 45-year-old woman with known Lynch syndrome (germline mutation in MLH1) presented in 2014 with abdominal bloating. Computed tomography (CT) showed a 4 cm pancreatic body mass encasing the portal vein, splenomesenteric confluence, and common hepatic artery with enlarged periportal lymph nodes present. Biopsy revealed pancreatic adenocarcinoma. The patient was deemed to have unresectable disease and treated with FOLFIRINOX (5-fluorouracil, folinic acid, irinotecan, oxaliplatin) and FOLFIRI with stable disease burden and declining tumor markers (Fig. 1). She also received stereotactic body radiation therapy (SBRT) 3300 cGy in five fractions.
Fig. 1
Fig. 1

Clinical Pattern of Acquired Resistance. Panel a shows CA 19–9 levels corresponding to the timeline showing therapy. Panel b shows axial CT images corresponding to the primary pancreatic mass before treatment with immunotherapy and during immunotherapy, and the ovarian mass that developed after 22 months of immunotherapy. Red circles indicate the pancreatic mass and the yellow circle indicates the ovarian mass. Panel b shows the pancreatic mass after chemotherapy and RT

In 2015, CT scan revealed progression of disease, along with a rise in CA19-9 and clinical symptoms. The patient was enrolled in a clinical trial (NCT 02471846) of an anti-PD-L1 antibody in combination with an IDO1 inhibitor (navoximod). She demonstrated a partial response as defined by RECIST 1.1 criteria with declining tumor markers and prompt resolution of symptoms. In 2017, 22 months after beginning therapy, CT scan revealed an increasing left ovarian cystic mass. There were no other sites of progressive disease. The patient underwent a total hysterectomy and bilateral salpingo-oophorectomy, appendectomy, omentectomy and pelvic lymphadenopathy. Pathology was consistent with a metastasis from the pancreas involving the endometrium and left ovary. Thereafter, the patient continued with PD-1 blockade therapy off protocol with no further progressive disease.

Genomic features of pre-treatment and treatment-resistant tumors

Tumor mutation profile and burden were determined through MSK-IMPACT, a next generation sequencing assay of somatic mutations in key cancer genes [16]. TMB was 50.2 mutations per megabase (mt/Mb) in the pretreatment sample and 21.1 mt/Mb in the acquired resistance sample (Table 1); both tumors were computationally consistent with microsatellite-instability high. Only the KRAS G12D and RNF43 G659Vfs*41 mutations were retained from the pre-treatment tumor in the treatment-resistant tumor. No copy number alterations were detected in either the pre-treatment or the acquired resistance tumor sample. There was no loss-of-function mutations or loss of heterozygosity (LOH) in the HLA genes, B2M, PTEN, JAK1, JAK2, or TAP1.
Table 1

Mutations in primary and metastatic lesions

Gene

Protein change

Mutation type

Primary Pancreas Lesion

KRAS

G12D

Missense_Mutation

RNF43

G659Vfs*41

Frame_Shift_Del

ARID1A

P1326Rfs*155

Frame_Shift_Del

STK11

P281Rfs*6

Frame_Shift_Del

B2M

S14Ffs*29

Frame_Shift_Del

MAP3K1

N1079Ifs*3

Frame_Shift_Del

ARID1A

A339Lfs*24

Frame_Shift_Del

CIC

P1529Lfs*91

Frame_Shift_Del

ERCC4

R689C

Missense_Mutation

PIK3R1

M1?

Translation_Start_Site

KMT2A

S2872*

Nonsense_Mutation

BCL2L11

S118Kfs*21

Frame_Shift_Ins

MLH1

X556_splice

Splice_Site

FANCA

P1444Rfs*3

Frame_Shift_Del

BRCA2

R2502C

Missense_Mutation

BCOR

S526 L

Missense_Mutation

BRCA2

K1191 M

Missense_Mutation

ALK

G1202Efs*56

Frame_Shift_Del

ZFHX3

A3407Lfs*78

Frame_Shift_Del

PTPRS

R1102H

Missense_Mutation

FLT1

R1305H

Missense_Mutation

AR

R280C

Missense_Mutation

ROS1

R1592C

Missense_Mutation

JAK3

P84Rfs*63

Frame_Shift_Del

PTPRT

I502T

Missense_Mutation

RECQL4

V155Sfs*25

Frame_Shift_Del

VTCN1

Y145H

Missense_Mutation

RAF1

Y458F

Missense_Mutation

SETD2

D1057N

Missense_Mutation

GATA2

P385S

Missense_Mutation

APC

R259Q

Missense_Mutation

APC

T1932A

Missense_Mutation

ARID1B

G314R

Missense_Mutation

ARID1B

A1002V

Missense_Mutation

RECQL4

G1166S

Missense_Mutation

RECQL4

A33V

Missense_Mutation

PAX5

R38C

Missense_Mutation

TGFBR1

V229D

Missense_Mutation

H3F3C

M120 V

Missense_Mutation

KMT2D

S1555F

Missense_Mutation

CREBBP

P2311L

Missense_Mutation

ZFHX3

T2667A

Missense_Mutation

PLCG2

L631R

Missense_Mutation

SPOP

N196K

Missense_Mutation

STK11

L285R

Missense_Mutation

INSR

R279H

Missense_Mutation

MEF2B

P106H

Missense_Mutation

TOP1

I457T

Missense_Mutation

NF2

K469R

Missense_Mutation

AR

V139M

Missense_Mutation

TRAF7

N174del

In_Frame_Del

Metastatic Site: Ovary/Endometrium

KRAS

G12D

Missense_Mutation

RNF43

G659Vfs*41

Frame_Shift_Del

TSC2

Q35*

Nonsense_Mutation

TP53

R273C

Missense_Mutation

STK11

X245_splice

Splice_Site

PBRM1

P1411Lfs*21

Frame_Shift_Del

BARD1

K208Rfs*4

Frame_Shift_Del

ATRX

D1940Ifs*15

Frame_Shift_Del

KMT2D

K4318Efs*15

Frame_Shift_Del

KMT2B

G1879Vfs*16

Frame_Shift_Del

NRAS

A66V

Missense_Mutation

CIC

R440H

Missense_Mutation

INSR

R1331C

Missense_Mutation

MYCN

R285Q

Missense_Mutation

BCL6

S434 N

Missense_Mutation

TNFAIP3

K759Qfs*10

Frame_Shift_Ins

RPS6KA4

RPS6KA4-BAD fusion

Fusion

FLT3

S188R

Missense_Mutation

ERBB2

H193N

Missense_Mutation

DOT1L

V170 L

Missense_Mutation

PTPRT

E917V

Missense_Mutation

HIST1H3F

T119A

Missense_Mutation

INHBA

A41T

Missense_Mutation

RXRA

G73C

Missense_Mutation

ARAF

E556G

Missense_Mutation

BAD

RPS6KA4-BAD fusion

Fusion

Pathological features of the treatment-resistant tumor

Immunohistochemistry (IHC) of the metastatic sample confirmed that the tumor was MMR-D, with loss of MLH1 and PMS2 expression (Fig. 2a-e). Histologically and immunophenotypically, the tumor exhibited features consistent with a metastasis of pancreatic origin including negative IHC staining for PAX8 (Fig. 2f), a marker typically associated with a Mullerian primary.
Fig. 2
Fig. 2

Immune Profiling of Metastatic Lesion. Metastatic pancreatic adenocarcinoma showing loss of MLH1 and PMS2 and increased immune cell infiltration. H&E section demonstrates a gland forming adenocarcinoma, morphologically compatible with pancreatic origin (a). By immunohistochemistry, the tumor cells show loss of staining for MLH1 (b) and PMS2 (c) and retained staining for MSH2 (d) and MSH6 (e). The tumor cells are also negative for PAX8 (f), in keeping with its non-Mullerian origin. Assessment of immune cell infiltration demonstrates florid CD8 positive T cells infiltrating the tumor epithelium and in the stroma surrounding the tumor epithelium (g). There is also prominent PD-1 positive immune cells (h) distributed similarly as the CD8 positive cells. PD-L1 expression is focally present in immune cells and in some tumor cells (i)

We were unable to assess immune cell infiltration with IHC in the pre-treatment tumor due to insufficient tissue. However, for the resected treatment-resistant metastasis, we found high levels of CD8+ T cells and PD-1 positive immune cells, with a moderate level of PD-L1 expression in both the immune cells and the tumor cells (Fig. 2g-i).

Discussion

Patients treated with immunotherapy may respond durably, fail to respond, or initially respond but subsequently develop acquired resistance. Acquired resistance to immunotherapy is a consequence of a number of tumor-extrinsic and tumor cell-intrinsic factors [17]. Tumor-extrinsic acquired resistance can be due to insufficient CD8+ T cell infiltration at the tumor microenvironment (TME) and immunosuppression in the TME by regulatory T cells, MDSCs, and TAMs [18]. Mechanisms of tumor-intrinsic acquired resistance include decreases in and loss of neoantigens [2, 4, 19], disruption of neoantigen presentation [3, 5, 20, 21], and resistance to interferon gamma [5].

The ovaries have been previously reported as a potential sanctuary site for malignant gastrointestinal metastases given their resistance to chemotherapy [22]. In this case, however, we did not see a deficit in immune cell infiltration at the ovarian site. Given the abundant CD8+ T cell infiltration, PD-1, and PD-L1 expression in the ovarian site, we speculate that the resistance mechanism is driven less by tumor-extrinsic factors and more by tumor-intrinsic factors.

In this case of acquired resistance to PDAC, the decrease in tumor mutation burden after treatment is likely reflective of immunoediting [2325]. However, the robust T cell infiltration within the resistant tumor microenvironment suggests a potential alternate mechanism restraining productive anti-tumor immunity. Through genomic profiling, we found no changes in loss of function or loss of heterozygosity in previously reported mechanisms of intrinsic resistance, including the HLA genes, B2M, PTEN, JAK1, JAK2, or TAP1. Similar cases in which the driver of resistance is unknown have been reported, and highlight the complexity of resistance in the context of immunotherapy and the need for larger, cooperative efforts to integrate analyses of these uncommon cases in order to reveal mechanistic insight [26].

In this PDAC patient, disease progression only occurred in the ovary, an uncommon site of metastases in PDAC [27]. The phenomenon and management of oligoprogression in the setting of acquired resistance to targeted therapy have been previously described in NSCLC [28]. But oligoprogression in the setting of acquired resistance to immunotherapy is less well described. A case series of acquired resistance to PD-1 axis inhibitors in 26 NSCLC patients found that a majority (89%) of these patients had recurrence limited to one or two sites of disease [7]. Isolated progression was also reported in the majority (78%) of 36 melanoma patients with acquired resistance to PD-1 blockade [29]. MMR-D patients under PD-1 blockade have been reported to develop acquired resistance, with tumors developing from occult sites such as the brain and the bone [1].

The present report has notable limitations. No clear mechanism of resistance was determined, although we speculate that immunoediting is a primary driving mechanism. Immunoediting is a dynamic dialogue between the immune system and the invading system that consists of elimination, equilibrium, and escape phases [30]. In the elimination phase, tumor cells are identified and eliminated by the immune system. In the equilibrium phase, the immune system is unable to eliminate all cancer cells but is able to contain further growth. In the escape phase, tumor cells variants are selected to proliferate in an immunologically intact environment. Genetic and epigenetic changes within these tumor cells grant additional resistance to immune elimination, allowing the tumor cells to grow. Further in vitro studies are needed to determine the specific acquired changes within the tumor and the selection pressure exerted by PD-L1 therapy. We also had insufficient pre-treatment tissue for immunopathologic testing to directly compare the phenotypic changes.

This is the first reported case, to our knowledge, of acquired immunotherapy resistance in PDAC with accompanying genomic and immune profiling of the metastasis. This case of oligoprogression in the setting of immunotherapy also highlights the feasibility of localized treatment followed by continuation of immunotherapy to sustain ongoing response elsewhere. A number of factors, including tumor heterogeneity, the specific resistance mechanism, and tissue-specific immunoregulation, likely influence the sites, extent, and rate of disease progression in acquired resistance to immunotherapy, and remain to be fully characterized [31].

Abbreviations

CRC: 

Colorectal cancer

CT: 

Computed tomography

IHC: 

Immunohistochemistry

LOH: 

Loss of heterozygosity

MDSC: 

Myeloid-derived suppressive cell

MMR-D: 

Mismatch repair deficient

NGS: 

Next generation sequencing

NSCLC: 

Non-small cell lung cancer

PDAC: 

Pancreatic ductal adenocarcinoma

SBRT: 

Stereotactic body radiation

TAM: 

Tumor-associated macrophages

TMB: 

Tumor mutation burden

TME: 

Tumor microenvironment

T-regs: 

T-regulatory cells

Declarations

Acknowledgments

The authors wish to gratefully acknowledge the patient and her family for allowing us to publish her case report.

Funding

This work was supported in part by the National Cancer Institute Cancer Center Core Grant No. P30-17 CA008748.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

All authors were involved in the generation of figures and writing of the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The patient described in this case signed a case report informed consent form which is available for review.

Consent for publication

The patient consented to publication of the case report.

Informed written consent was obtained from patient for publication of this case. Consent is available upon request.

Competing interests

Eileen M. O'Reilly (EOR): Research Funding Celgene, Sanofi, ActaBiologica, AstraZenica, Silenseed, Genentech-Roche. Consulting: Targovax, Celgene, Bayer. Matthew D. Hellman (MDH) receives research funding from Bristol-Myers Squibb; is paid consultant to Merck, Bristol-Myers Squibb, AztraZeneca, Genentech/Roche, Janssen, Nektar, Syndax, Mirati, and Shattuck Labs; receives travel support/honoraria from AztraZeneca and BMS; and a patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx.Luis A. Diaz (LAD) is a member of the board of directors of Personal Genome Diagnostics (PGDx) and Jounce Therapeutics. LAD holds equity in PapGene, Personal Genome Diagnostics (PGDx) and Phoremost. He is a paid consultant for Merck, PGDx and Phoremost. LAD is an inventor of licensed intellectual property related to technology for circulating tumor DNA analyses and mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. These licenses and relationships are associated with equity or royalty payments to LAD. The terms of all these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. In addition, in the past 5 years, LAD has participated as a paid consultant for one-time engagements with Caris, Lyndra, Genocea Biosciences, Illumina and Cell Design Labs. Jedd Wochok (JD) Consultant for: Adaptive Biotech; Advaxis; Amgen; Apricity; Array BioPharma; Ascentage Pharma;Astellas; Beigene; Bristol Myers Squibb; Celgene; Chugai; Elucida; Eli Lilly; F Star; Genentech; Imvaq; Kleo Pharma; MedImmune; Merck; Neon Therapuetics; Ono; Polaris Pharma; Polynoma; Psioxus; Puretech; Recepta; Trieza; Sellas Life Sciences; Serametrix; Surface Oncology; Syndax. Research support: Bristol Myers Squibb; Medimmune; Merck Pharmaceuticals; Genentech. Equity in: Potenza Therapeutics; Tizona Pharmaceuticals; Adaptive Biotechnologies; Elucida; Imvaq; Beigene; Trieza.Zsofia Stadler (ZK): Immediate Family Member, Ophthalmology Consulting/Advisory Role: Allergan, Adverum Biotechnologies, Alimera Sciences, Biomarin, Fortress Biotech, Genentech, Novartis, Optos, Regeneron, Regenxbio, Spark Therapeutics. The other authors (ZIH, MV, JS) declare that they have no competing interests.

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Authors’ Affiliations

(1)
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
(2)
Division of Solid Tumor Oncology, New York, NY, USA
(3)
Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering, New York, NY, USA
(4)
Department of Medicine, Weill Cornell Medical College, New York, NY, USA
(5)
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA
(6)
Department of Pathology, Weill Cornell Medical College, New York, NY, USA
(7)
David M. Rubenstein Center for Pancreatic Cancer Research, New York, NY, USA

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Copyright

© The Author(s). 2018

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