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Text Content

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 * Home
 * MMR Status Matters
 * Potential of PARPi
 * Stay Informed





IN PMMR ENDOMETRIAL CANCER, CAN PARP INHIBITION AN IMMUNE RESPONSE?


MMR STATUS MAY PREDICT RESPONSE TO IMMUNOTHERAPY1-4

dMMR

dMMR/MSI-H tumors, comprising 20%-30% of endometrial cancer cases, typically
have a higher tumor mutational burden and neoantigen load.1,4-10



Therefore, they are associated with a more immunologically active, or “primed”,
tumor microenvironment.4,8-11


IMMUNOLOGICALLY PRIMED TUMOR MICROENVIRONMENTS ARE CHARACTERIZED BY:

Higher levels of tumor-infiltrating CD8+ T cells and natural killer (NK)
cells8-14

Lower levels of immunosuppressive immune cells and cytokines13-15



dMMR/MSI-H tumors are responsive to immune checkpoint inhibitors, which in
preclinical studies have been shown to work by releasing T cells from the
inhibitory effects of immune checkpoint signaling pathways such as
PD-1/PD-L1.1-4,11

pMMR

pMMR/MSS tumors, which form the majority (70%-80%) of endometrial cancer cases,
typically have a lower tumor mutational burden and neoantigen load.1,4-10



They are associated with a significantly less immunoreactive, or “unprimed”,
tumor microenvironment.9-12,16


IMMUNOLOGICALLY UNPRIMED TUMOR MICROENVIRONMENTS ARE CHARACTERIZED BY:

Lower levels of tumor-infiltrating lymphocytes9-14

Presence of immunosuppressive immune cells and cytokines12-14,17



pMMR/MSS tumors are heterogeneous and are thought to have more variable and
hampered immune priming, as shown in preclinical studies.2,3,11,12 Consequently,
the antitumor effects from immune checkpoint inhibitors tend to be
limited.1-4,12,13,18

Primed
tumor

Immunologically primed dMMR tumors are responsive to immunotherapy.1-4,10-13


Unprimed
tumor

Immunologically unprimed pMMR tumors show limited response to
immunotherapy.1-4,11-13,16



Is there a way to potentially boost the immunogenicity of unprimed pMMR tumors?


PARP INHIBITION MAY ENHANCE IMMUNE PRIMING OF PMMR TUMORS, BASED ON PRECLINICAL
EVIDENCE18-22

+PARPi

PARPi is one of multiple mechanisms under investigation in combination with
immune checkpoint blockade for endometrial cancer.23-27 Others include
chemotherapy, TKIs, and VEGF inhibitors.25-27

The priming potential of PARP inhibition

Watch how PARPi helps prime pMMR tumors to enhance the effects of immunotherapy.


TRANSCRIPT

Frame 1

VISUAL: Video opens with title fading in over a white and gray gradient
background, followed shortly afterwards with the rest of the text and the
AstraZeneca logo.

TEXT ON SCREEN:

In pMMR endometrial cancer, Can PARP inhibition spark an immune response?

Presented by AstraZeneca

Frame 2

VISUAL: The first portion of the header text arrives on screen, as a light
brown, roughly sphere-shaped dMMR tumor inside a yellow bubble enters and
settles towards the left of the screen. The other two lines of text, accompanied
by an up arrow, follow in tandem, enlarged at first and then shrinking into
place below the tumor.

TEXT ON SCREEN:

In endometrial cancer, differences in immune priming between dMMR/MSI-H...

dMMR

 * More immunologically primed4-8
 * Greater response to immunotherapies1-9

Frame 3

VISUAL: The dMMR tumor remains as a similar looking pMMR tumor inside a pink
bubble enters and settles beside it on the right. Simultaneously, the second
half of the header text enters and replaces the first half. The last two lines
of text, accompanied by a down arrow, then follow in tandem, enlarged at first
and then shrinking into place below the pMMR tumor.

TEXT ON SCREEN:

...and pMMR/MSS tumors may account for discrepancies in responsiveness to
immunotherapies.1-10

dMMR

 * More immunologically primed4-8
 * Greater response to immunotherapies1-9

pMMR

 * Less immunologically primed5-8
 * Limited response to immunotherapies1-10

Frame 4

VISUAL: New text animates on, followed by a green question mark. The question
mark enlarges and moves downward as the lines of text slide past each other. The
text and question mark then fade offscreen together.

TEXT ON SCREEN: Why are dMMR tumors potentially more responsive to
immunotherapies?

Frame 5

Another, smaller dMMR tumor enters from the left side of the screen and moves
across, towards the right, enlarging as it moves.

TEXT ON SCREEN: N/A

Frame 6

VISUAL: Text animates onscreen, accompanied by an arrow that moves upwards. At
the same time, a tumor microenvironment, marked by a yellow bubble, appears
around the enlarged dMMR tumor made up of smaller, circular dMMR tumor cells.
Various immune cells (green immunostimulatory antitumor immune cells and
signals, pink cytotoxic T cells, and purple immunosuppressive pro-tumor immune
cells and signals) enter just afterwards on the left side. The tumor label text
appears last on the upper right corner of the screen and remains for the rest of
the dMMR section.

TEXT ON SCREEN:

dMMR tumors have a higher tumor mutational burden and neoantigen load, due to
their impaired mismatch repair4-7

Select elements within the tumor microenvironment

 * Immunostimulatory antitumor immune cells and signals
 * Cytotoxic T cells
 * Immunosuppressive pro-tumor immune cells and signals

Frame 7

VISUAL: More text animates in and replaces the text from the previous frame.
Simultaneously, the immunostimulatory and immunosuppressive immune cells and
signals and the cytotoxic T cells on the left begin to move towards the tumor,
getting smaller as they approach. More immune cells enter from the surrounding
microenvironment and move toward the tumor.

TEXT ON SCREEN: which is associated with an immunologically primed tumor
microenvironment characterized by higher levels of immunostimulatory cells and
signals.4-9,11

Frame 8

VISUAL: New text, accompanied by an "X," animates onscreen to replace the
previous text as the immune cells on and around the tumor on the right continue
to move within the tumor microenvironment.

TEXT ON SCREEN: However, preexisting immune presence within the microenvironment
does not lead to robust tumor cell death,

Frame 9

VISUAL: The rest of the text builds to complete the sentence as the immune cells
continue to move around and within the tumor microenvironment.

TEXT ON SCREEN: However, preexisting immune presence within the microenvironment
does not lead to robust tumor cell death, in part because of inhibitory immune
checkpoint signaling that limits cytotoxic T-cell activity.5,6,12,13

Frame 10

VISUAL: New text to replace the previous animates onscreen to the left of the
tumor and immune cells, and an orange chemotherapy and light orange immune
checkpoint inhibitor appear. The chemotherapy and immune checkpoint inhibitor
move toward the tumor as more enter from the tumor microenvironment to join the
immune cells still present there as the microenvironment bubble starts to turn
from yellow to green.

TEXT ON SCREEN: The combination of immunotherapy and chemotherapy can increase T
cell–mediated tumor cell killing via enhanced immune response,

Frame 11

VISUAL: The rest of the sentence builds onscreen, and the tumor microenvironment
continues to turn green as the tumor and all elements around it shrink. After a
pause, all objects and text fade offscreen.

TEXT ON SCREEN:

The combination of immunotherapy and chemotherapy can increase T cell–mediated
tumor cell killing via enhanced immune response, leading to robust antitumor
activity.4-10,12*

*Demonstrated in preclinical models.

Frame 12

VISUAL: New text animates on screen, followed by a green question mark. The
question mark enlarges and moves downward as the lines of text slide past each
other. The text and question mark then fade offscreen together.

TEXT ON SCREEN: Why do pMMR tumors typically show a more limited response to
immunotherapies?

Frame 13

VISUAL: New text animates on screen. After a pause, the screen transitions.

TEXT ON SCREEN: pMMR tumors are heterogeneous and are thought to have more
variable and hampered immune priming.2-8

Frame 14

VISUAL: More text animates on screen to replace the text from the previous
frame, accompanied by a downward arrow. Simultaneously, a large pMMR tumor made
up of circular pMMR tumor cells enters the frame from the right and moves
towards the left, growing as it moves. Subsequently, various immune cells (green
immunostimulatory antitumor immune cells and signals, pink cytotoxic T cells,
and purple immunosuppressive pro-tumor immune cells and signals) enter on the
left side and a large red tumor microenvironment bubble encircles the tumor. The
tumor label text appears last on the upper right corner of the screen and
remains for the rest of the pMMR section.

TEXT ON SCREEN: Most pMMR tumors typically have lower tumor mutational burden
and neoantigen load compared to dMMR tumors.4-8

Frame 15

VISUAL: The immunostimulatory and immunosuppressive immune cells and signals and
the cytotoxic T cells on the left begin to move towards the tumor, getting
smaller as they approach and ultimately landing on the tumor. Additional immune
cells approach from within the microenvironment and land on the tumor. Text
animates in on the left to replace the text from the previous frame and
continues to build as the cells move around the tumor within the
microenvironment. A down arrow serves as a bullet point for the first phrase and
an up arrow serves as a bullet for the second phrase.

TEXT ON SCREEN:

This is associated with an immunologically unprimed tumor microenvironment
characterized by5-8:

 * fewer infiltrating lymphocytes5-9,11
 * more immunosuppressive pro-tumor immune cells and signals8,9,11,14

Frame 16

VISUAL: Text fades onscreen on the left of the tumor and immune cells to replace
the previous text, and an orange chemotherapy and a light orange immune
checkpoint inhibitor appear. More chemotherapy and immune checkpoint inhibitors
enter from the microenvironment and move toward the tumor until they all land.
Once they arrive, they remain moving slightly around and within the tumor as the
microenvironment turns from red to yellow. After a pause, all elements fade off.

TEXT ON SCREEN:

Therefore, chemotherapy and immunotherapy lead to limited antitumor immune
response and tumor cell killing.1-10*

*Demonstrated in preclinical models.

Frame 17

VISUAL: New text animates on screen, followed by a green question mark. The
question mark enlarges and moves downward as the lines of text slide past each
other. The text and question mark then fade offscreen together.

TEXT ON SCREEN: Is there a way to potentially boost the immunogenicity of
unprimed pMMR tumors?

Frame 18

VISUAL: New text animates onscreen. After a pause, the screen transitions.

TEXT ON SCREEN: PARP inhibition is one of multiple mechanisms currently under
investigation15-19

Frame 19

VISUAL: The large pMMR tumor and its associated immune cells, chemotherapy, and
immune checkpoint inhibitors reappear within the yellow tumor microenvironment
to the right. Chemotherapy fades out. New text animates onscreen as a blue PARPi
icon appears on the right side. The PARPi moves towards the tumor as more PARPi
and chemotherapy icons enter in the microenvironment and move toward the tumor.

TEXT ON SCREEN: PARP inhibition induces DNA damage, leading to tumor cell death
and further immune priming20-22

Frame 20

VISUAL: New text animates onscreen to the left to replace the previous text, as
PARPi icons continue approaching the pMMR tumor until one enters the center of
the tumor. The tumor microenvironment starts to change from yellow to green.

TEXT ON SCREEN:

The addition of PARP inhibition to chemotherapy and immunotherapy may boost
anti-PD-L1–mediated immune activation,10,21-23*

*Based on preclinical findings in other cancer types.

Frame 21

VISUAL: New text animates on the left side to replace the previous text. As the
PARPi, immune cells, and immune checkpoint inhibitors continue to move around
the pMMR tumor, the tumor microenvironment continues to turn green.

TEXT ON SCREEN:

thereby enhancing the activity of immune checkpoint inhibition.10,21-23*

*Based on preclinical findings in other cancer types.

Frame 22

VISUAL: Once the tumor microenvironment has turned fully green, the pMMR tumor
begins to shrink and the PARPi, immune checkpoint inhibitors, and immune cells
around it follow until it fades out. After the tumor disappears, all text and
icons fade off.

TEXT ON SCREEN:

thereby enhancing the activity of immune checkpoint inhibition.10,21-23*

*Based on preclinical findings in other cancer types.

Frame 23

VISUAL: Text appears onscreen. After a pause, it fades off.

TEXT ON SCREEN: Research is actively ongoing to investigate new regimens that
better address the molecular and histological heterogeneity in pMMR endometrial
cancer.

Frame 24

VISUAL: Relevant video definitions and reference sources fade onscreen. After a
pause, they fade off.

TEXT ON SCREEN:

dMMR=mismatch repair deficient; MSI-H=microsatellite instability-high;
MSS=microsatellite stable; PARP=poly (ADP-ribose) polymerase; PARPi=poly
(ADP-ribose) polymerase inhibition; pMMR=mismatch repair proficient.

References: 1. Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus
chemotherapy in advanced endometrial cancer. N Engl J Med.
2023;388(23):2159-2170. doi:10.1056/NEJMoa2302312 2. Antill Y, Kok P-S, Robledo
K, et al; Australia New Zealand Gynaecological Oncology Group (ANZGOG). Clinical
activity of durvalumab for patients with advanced mismatch repair-deficient and
repair-proficient endometrial cancer: a nonrandomized phase 2 clinical trial. J
Immunother Cancer. 2021;9(6):e002255. doi:10.1136/jitc-2020-002255 3. Oaknin A,
Gilbert L, Tinker AV, et al. Safety and antitumor activity of dostarlimab in
patients with advanced or recurrent DNA mismatch repair deficient/microsatellite
instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial
cancer: interim results from GARNET–a phase I, single-arm study. J Immunother
Cancer. 2022;10(1):e003777. doi:10.1136/jitc-2021-003777 4. Song Y, Gu Y, Hu X,
Wang M, He Q, Li Y. Endometrial tumors with MSI-H and dMMR share a similar tumor
immune microenvironment. OncoTargets Ther. 2021;14:4485-4497.
doi:10.2147/OTT.S324641 5. Howitt BE, Shukla SA, Sholl LM, et al. Association of
polymerase e-mutated and microsatellite-instable endometrial cancers with
neoantigen load, number of tumor-infiltrating lymphocytes, and expression of
PD-1 and PD-L1. JAMA Oncol. 2015;1(9):1319-1323. doi:10.1001/jamaoncol.2015.2151
6. Asaka S, Yen T-T, Wang T-L, Shih I-M, Gaillard S. T cell-inflamed phenotype
and increased Foxp3 expression in infiltrating T-cells of mismatch-repair
deficient endometrial cancers. Mod Pathol. 2019;32(4):576-584.
doi:10.1038/s41379-018-0172-x 7. Eggink FA, Van Gool IC, Leary A, et al.
Immunological profiling of molecularly classified high-risk endometrial cancers
identifies POLE-mutant and microsatellite unstable carcinomas as candidates for
checkpoint inhibition. Oncoimmunology. 2016;6(2):e1264565.
doi:10.1080/2162402X.2016.1264565 8. Galon J, Bruni D. Approaches to treat
immune hot, altered and cold tumours with combination immunotherapies. Nat Rev
Drug Discov. 2019;18(3):197-218. doi:10.1038/s41573-018-0007-y 9. Rizzo A.
Immune checkpoint inhibitors and mismatch repair status in advanced endometrial
cancer: elective affinities. J Clin Med. 2022;11(13):3912.
doi:10.3390/jcm11133912 10. Eskander RN, Powell MA. Immunotherapy as a treatment
strategy in advanced stage and recurrent endometrial cancer: review of current
phase III immunotherapy clinical trials. Ther Adv Med Oncol.
2021;13:17588359211001199. doi:10.1177/17588359211001199 11. Le Gouvello S,
Bastuji-Garin S, Aloulou N, et al. High prevalence of Foxp3 and IL17 in
MMR-proficient colorectal carcinomas. Gut. 2008;57(6):772-779.
doi:10.1136/gut.2007.123794 12. Wei SC, Duffy CR, Allison JP. Fundamental
mechanisms of immune checkpoint blockade therapy. Cancer Discov.
2018;8(9):1069-1086. doi:10.1158/2159-8290.CD-18-0367 13. Daly RJ, Scott AM,
Klein O, Ernst M. Enhancing therapeutic anti-cancer responses by combining
immune checkpoint and tyrosine kinase inhibition. Mol Cancer. 2022;21(1):189.
doi:10.1186/s12943-022-01656-z 14. Dai Y, Zhao L, Hua D, et al. Tumor immune
microenvironment in endometrial cancer of different molecular subtypes: evidence
from a retrospective observational study. Front Immunol. 2022;13:1035616.
doi:10.3389/fimmu.2022.1035616 15. A study to evaluate dostarlimab plus
carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel in
participants with recurrent or primary advanced endometrial cancer (RUBY).
ClinicalTrials.gov identifier: NCT03981796. Updated August 14, 2023. Accessed
February 26, 2024. https://clinicaltrials.gov/study/NCT03981796 16. Durvalumab
with or without olaparib as maintenance therapy after first-line treatment of
advanced and recurrent endometrial cancer (DUO-E). ClinicalTrials.gov
identifier: NCT04269200. Updated December 5, 2023. Accessed February 26, 2024.
https://clinicaltrials.gov/study/NCT04269200 17. Marth C, Tarnawski R,
Tyulyandina A, et al. Phase 3, randomized, open-label study of pembrolizumab
plus lenvatinib versus chemotherapy for first-line treatment of advanced or
recurrent endometrial cancer: ENGOT-en9/LEAP-001. Int J Gynecol Cancer.
2022;32(1):93-100. doi:10.1136/ijgc-2021-003017 18. Liao Y, Zhu C, Song X, et
al. Efficacy of PD-1 inhibitor combined with bevacizumab in treatment of
advanced endometrial cancer patients with mismatch repair deficiency
(dMMR)/high-level microsatellite instability (MSI-H). Med Sci Monit.
2022;28:e934493. doi:10.12659/MSM.934493 19. Mirza MR, Chase DM, Slomovitz BM,
et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl
J Med. 2023;388(23):2145-2158. doi:10.1056/NEJMoa2216334 20. Stewart RA, Pilié
PG, Yap TA. Development of PARP and immune-checkpoint inhibitor combinations.
Cancer Res. 2018;78(24):6717-6725. doi:10.1158/0008-5472.CAN-18-2652 21. Sato H,
Niimi A, Yasuhara T, et al. DNA double-strand break repair pathway regulates
PD-L1 expression in cancer cells. Nat Commun. 2017;8(1):1751.
doi:10.1038/s41467-017-01883-9 22. Shen J, Zhao W, Ju Z, et al. PARPi triggers
the STING-dependent immune response and enhances the therapeutic efficacy of
immune checkpoint blockade independent of BRCAness. Cancer Res.
2019;79(2):311-319. doi:10.1158/0008-5472.CAN-18-1003 23. Jiao S, Xia W,
Yamaguchi H, et al. PARP inhibitor upregulates PD-L1 expression and enhances
cancer-associated immunosuppression. Clin Cancer Res. 2017;23(14):3711-3720.
doi:10.1158/1078-0432.CCR-16-3215

Frame 25

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TEXT ON SCREEN: ©2024 AstraZeneca. All rights reserved. US-84627 Last Updated
3/24

 

Evidence from preclinical studies suggests that the addition of PARPi may help
immunologically prime certain types of pMMR tumors.18-22

PARPi induces DNA damage that leads to tumor cell death20,21,28

When combined with chemotherapy and immune checkpoint inhibition, PARPi may
enhance PD-(L)1 mediated immune activation and increase tumor cell killing18-21

PARPi may enhance the effects of immune checkpoint inhibition18-21

AstraZeneca is committed to transforming the treatment landscape and expanding
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CD8+=cluster of differentiation 8–positive; dMMR=mismatch repair deficient;
IO=immunotherapy; MMR=mismatch repair; MSI-H=microsatellite instability-high;
MSS=microsatellite stable; PARP=poly (ADP-ribose) polymerase; PARPi=poly
(ADP-ribose) polymerase inhibition; PD-1=programmed cell death protein 1;
PD-L1=programmed death-ligand 1; pMMR=mismatch repair proficient; TKI=tyrosine
kinase inhibitor; VEGF=vascular endothelial growth factor.

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Yasuhara T, et al. DNA double-strand break repair pathway regulates PD-L1
expression in cancer cells. Nat Commun. 2017;8(1):1751.
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the STING-dependent immune response and enhances the therapeutic efficacy of
immune checkpoint blockade independent of BRCAness. Cancer Res.
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carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel in
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ClinicalTrials.gov identifier: NCT03981796. Updated August 14, 2023. Accessed
February 26, 2024. https://clinicaltrials.gov/study/NCT03981796 24. Durvalumab
with or without olaparib as maintenance therapy after first-line treatment of
advanced and recurrent endometrial cancer (DUO-E). ClinicalTrials.gov
identifier: NCT04269200. Updated December 5, 2023. Accessed February 26, 2024.
https://clinicaltrials.gov/study/NCT04269200 25. Marth C, Tarnawski R,
Tyulyandina A, et al. Phase 3, randomized, open-label study of pembrolizumab
plus lenvatinib versus chemotherapy for first-line treatment of advanced or
recurrent endometrial cancer: ENGOT-en9/LEAP-001. Int J Gynecol Cancer.
2022;32(1):93-100. doi:10.1136/ijgc-2021-003017 26. Liao Y, Zhu C, Song X, et
al. Efficacy of PD-1 inhibitor combined with bevacizumab in treatment of
advanced endometrial cancer patients with mismatch repair deficiency
(dMMR)/high-level microsatellite instability (MSI-H). Med Sci Monit.
2022;28:e934493. doi:10.12659/MSM.934493 27. Mirza MR, Chase DM, Slomovitz BM,
et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl
J Med. 2023;388(23):2145-2158. doi:10.1056/NEJMoa2216334 28. Stewart RA, Pilié
PG, Yap TA. Development of PARP and immune-checkpoint inhibitor combinations.
Cancer Res. 2018;78(24):6717-6725. doi:10.1158/0008-5472.CAN-18-2652

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