Combining Against Cancer | Editorials

Cancer cells have many ways to stop the immune system from recognizing and destroying them.¹ Some of the biological components that may have a role in how the immune system identifies and attacks cancer cells include:

PD-1 and TIGIT: Receptors found at high levels on the surface of certain immune cells in various types of cancer, that are part of a pathway that can block recognition and destruction of cancer cells.¹

Imagine cars — as our body’s immune cells — heading towards the Golden Gate Bridge to get to the other side in order to attack and destroy cancer cells.

As they approach the bridge, think of PD-1 and TIGIT like a stop sign and a red traffic light, respectively, that block the cars from crossing the bridge.
ADENOSINE: A compound that can accumulate in the area surrounding cancer cells, and is made by receptors found at high levels on cancer cells. It binds to other receptors on the surface of immune cells, which deactivates them from attacking cancer cells.²

Picture the cars are now driving on the bridge, but a thick, dense fog – this is like adenosine – rolls in and doesn’t allow the cars to see clearly to get across the bridge as they slowly roll to a stop, preventing them from attacking and destroying the cancer cells on the other side.

Other biological components are also involved helping cancer cells survive, such as:

HIF2α: Tumors often have low oxygen levels, and this regulator can promote growth of tumors in these conditions.³

In many cancers, more than one of these biological components are involved in preventing cancer cell death.^4,5,6 Research is underway to determine whether stopping more than one of these biological components at the same time may improve the body’s ability to detect and destroy cancer cells.

Take a closer look at some different cancer types where a biology-driven, combination approach may lead to the development of new treatment approaches and help address unmet needs for people with cancer.

According to the American Cancer Society:

Non-small cell lung cancer

(NSCLC) represents about

Non-small cell lung cancer (NSCLC) represents about

85%

of all lung cancer diagnoses.⁷

Lung cancer is the:

2^nd

most common

type of cancer⁷

^#1

cause of cancer-

related deaths.⁷

Current Status of Immunotherapy in NSCLC

Cancer treatment primarily depends on disease stage, which characterizes how big the tumor is and if it has spread throughout the body.⁸ One treatment approach is immunotherapy, which harnesses the body’s natural immune system to attack and destroy the cancer.¹

Anti-PD-1s are a type of immunotherapy used to treat different stages of cancer.⁹ They are believed to work by blocking the PD-1 pathway and activating immune cells to attack cancer cells.¹

Combination Strategies Under Investigation

In many people, however, the cancer can continue to grow even with anti-PD-1 treatment.¹ Researchers are working to understand if combining multiple investigational medicines, that each target different immune-evading pathways, may lead to the development of new medicines to treat people with cancer.

TIGIT, like PD-1, has been found at higher levels on the surface of immune cells in people with NSCLC and is associated with worse clinical outcomes.^10,11 TIGIT and PD-1 may both play a role in controlling anti-cancer immune responses, but they do so in different ways.^5,12

Clinical trials are ongoing to understand if the combination of an anti-TIGIT and an anti-PD-1 can activate the immune system to destroy cancer cells better than anti-PD-1 alone, much like, in the analogy of a car crossing the bridge, removing both the stop sign and traffic light is important for the cars, or immune cells, to cross the bridge and attack cancer cells.

Adenosine can be found at high levels in NSCLC and may disable immune cells from recognizing and attacking cancer cells.¹³ Adenosine also acts on anti-cancer immunity, but in a different way than the PD-1 and TIGIT pathways. It is believed adenosine can deactivate a broader set of immune cells.^14,15 Reducing adenosine along with blocking TIGIT and PD-1, may help immune cells to attack cancer cells.^16,17

In the analogy of a car crossing the bridge, lifting the fog (adenosine) may help the cars, or immune cells remain active. If the fog is lifted and both the stop sign (PD-1) and red traffic light (TIGIT) are also removed, the combined approach may help the cars, or immune cells, cross the bridge to attack and destroy the cancer cells.

Chemotherapy, a common cancer treatment that attacks fast-growing cells, still remains an important component of therapy.^18,19 In some cases, chemotherapy, in addition to removing barriers to immune cell function, may further help the body destroy fast-growing cancer cells.

Clinical trials are ongoing to understand if combining different investigational medicines to stop more than one biological pathway at the same time, with or without chemotherapy, may improve the ability of the immune system to detect and destroy cancer cells and lead to new treatment options.

Colorectal cancer (CRC) is any cancer that starts in the colon or rectum, collectively known as the large intestine.²⁰

According to the American Cancer Society, CRC is the:

3^rd

most common diagnosed cancer in the United States^*²⁰

2^nd

leading cause of cancer-related deaths.²⁰

^*Excluding skin cancers

Current Status of Immunotherapy in CRC

Cancer treatment primarily depends on disease stage, which characterizes how big the tumor is and if it has spread throughout the body.⁸ One treatment approach is immunotherapy, which harnesses the body’s natural immune system to attack and destroy the cancer.¹

Anti-PD-1s are a type of immunotherapy that are typically used at later stages of disease for people who have certain genetic changes in their cancer cells.²¹ They are believed to work by blocking the PD-1 pathway and activating immune cells to attack cancer cells.¹

Combination Strategies Under Investigation

In many people, however, the cancer can continue to grow even with anti-PD1 treatment.²² Researchers are working to understand if combining anti-PD1 with other investigational medicines that each target different immune-evading pathways may lead to the development of new medicines to treat more people with metastatic cancer, or cancer that has spread to other parts of the body.

Increased levels of adenosine surrounding CRC cells is believed to contribute to cancer growth and suppress immune activity.²³ Adenosine also acts on anti-cancer immunity, but in a different way than the PD-1 pathway. It is believed that adenosine can deactivate a broader set of immune cells.^14,15

Reducing adenosine along with blocking PD-1, may help immune cells to attack cancer cells.^16,17 In the analogy of a car crossing the bridge, lifting the fog (adenosine) may help the cars, or immune cells, remain active. If the fog is lifted and the stop sign (PD-1) is removed, the combined approach may help the cars, or immune cells, cross the bridge to attack and destroy the cancer cells.

Chemotherapy, a common cancer treatment that attacks fast-growing cells, still remains an important component of therapy.^18,19 In some cases, chemotherapy, in addition to removing barriers to immune cell function, may further help the body destroy fast-growing cancer cells.

Clinical trials are ongoing to understand if combining different investigational medicines to stop more than one biological pathway at the same time, with or without chemotherapy, may improve the ability of the immune system to detect and destroy cancer cells and lead to new treatment options.

Upper gastrointestinal (GI) cancer includes cancers that occur in the stomach, esophagus (the tube that carries food and drinks from the throat to the stomach) and gastroesophageal junction (where the esophagus connects to the stomach).²⁴

More than 90% of gastric cancers are adenocarcinomas, a type of cancer that forms in tissues which line certain internal organs and release fluids, like those that help with digestion.^25,26
A majority (up to 80%) of esophageal cancers are adenocarcinomas.^27,28

According to the National Cancer Institute, upper GI cancers are the:

2^nd

most common cause of death among digestive system cancers.²⁴

They have poor 5-year survival rates when diagnosed in later stages.²⁹

Current Status of Immunotherapy in Upper GI Cancer

Cancer treatment primarily depends on disease stage, which characterizes how big the tumor is and if it has spread throughout the body.⁸ One treatment approach is immunotherapy, which harnesses the body’s natural immune system to attack and destroy the cancer.¹

Anti-PD-1s are a type of immunotherapy that are typically used at later stages of disease, including for people who have certain genetic changes in their cancer cells.^30,31 They are believed to work by blocking the PD-1 pathway and activating immune cells to attack cancer cells.¹

Combination Strategies Under Investigation

In many people, however, the cancer can continue to grow even with anti-PD-1 treatment.^32,33 Researchers are working to understand if combining multiple investigational medicines, that each target different immune-evading pathways, may lead to the development of new medicines to treat people with cancer.

TIGIT, like PD-1, has been found at higher levels on the surface of immune cells in people with upper GI cancers, and is associated with worse clinical outcomes.^34,35,36,37 TIGIT and PD-1 may both play a role in controlling anti-cancer immune response, but they do so in different ways.^5,12

Clinical trials are ongoing to understand if the combination of an anti-TIGIT and an anti-PD-1 can activate the immune system to destroy cancer cells better than anti-PD-1 alone, much like, in the analogy of a car crossing the bridge, removing both the stop sign and traffic light is important for the cars, or immune cells to cross the bridge and attack cancer cells.

Adenosine is believed to play a key role in suppressing immune activity in certain upper GI cancers, contributing to the growth and survival of cancer cells.^38,39 Adenosine also acts on anti-cancer immunity, but in a different way than the PD-1 and TIGIT pathways. It is believed adenosine can deactivate a broader set of immune cells.^14,15 Reducing adenosine along with blocking TIGIT and PD-1, may help immune cells to attack cancer cells.^16,17

In the analogy of a car crossing the bridge, lifting the fog (adenosine) may help cars, or immune cells remain active. If the fog is lifted and the stop sign (PD-1) and red traffic light (TIGIT) are also removed, the combined approach may help the cars, or immune cells cross the bridge to attack and destroy cancer cells.

Chemotherapy, a common cancer treatment that attacks fast-growing cells, still remains an important component of therapy.^18,19 In some cases, chemotherapy in addition to removing barriers to immune cell function, may further help the body destroy fast-growing cancer cells.

Clinical trials are ongoing to understand if combining different investigational medicines to stop more than one biological pathway at the same time, with or without chemotherapy, may improve the ability of the immune system to detect and destroy cancer cells, and lead to new treatment options.

Pancreatic cancer occurs in the pancreas, an organ that sits behind the stomach and helps with digestion and controlling blood sugar.⁴⁰

Over 90% of pancreatic cancers are adenocarcinomas, a type of cancer that forms in tissues which line certain internal organs and release fluids, like those that help with digestion.^40,41

Pancreatic cancer is one of the most aggressive cancers with an extremely poor prognosis and an average 5-year relative survival rate of

12%⁴²

Over 80% of pancreatic cancers are diagnosed at late stage⁴³

There have been limited advancements for treating pancreatic cancer and chemotherapy has been the standard of care for more than 30 years, which is why new treatment options are needed.^44,45,46

Current Status of Immunotherapy in Pancreatic Cancer

Cancer treatment primarily depends on disease stage, which characterizes how big the tumor is and if it has spread throughout the body.⁸ One treatment approach is immunotherapy, which harnesses the body’s natural immune system to attack and destroy the cancer.¹

Anti-PD-1s are a type of immunotherapy that are typically used at later stages of disease for people who have certain genetic changes in their cancer cells.⁴⁷ They are believed to work by blocking the PD-1 pathway and activating immune cells to attack cancer cells.¹

Combination Strategies Under Investigation

In many people, however, the cancer can continue to grow even with anti-PD-1 treatment.^48,49,50 Researchers are working to understand if combining anti-PD-1 with other investigational medicines that each target different immune-evading pathways, may lead to the development of new medicines to treat more people with metastatic cancer, or cancer that has spread to other parts of the body.

Adenosine is believed to contribute to suppressed immune activity around pancreatic cancer cells and increased adenosine activity could contribute to worse clinical outcomes.^51,52 Adenosine also acts on anti-cancer immunity, but in a different way than the PD-1 pathway. It is believed that adenosine can deactivate a broader set of immune cells.^14,15 Reducing adenosine along with blocking PD-1 may help immune cells to attack cancer cells.^16,17

In the analogy of a car crossing the bridge, lifting the fog (adenosine) may help cars, or immune cells, remain active. If the fog is lifted and the stop sign (PD-1) is removed, the combined approach may help the cars, or immune cells, cross the bridge to attack and destroy cancer cells.

Chemotherapy, a common cancer treatment that attacks fast-growing cells, still remains an important component of therapy.^18,19 In some cases, chemotherapy in addition to removing barriers to immune cell function, may further help the body destroy fast-growing cancer cells.

Clinical trials are ongoing to understand if combining different investigational medicines to stop more than one biological pathway at the same time, with or without chemotherapy, may improve the ability of the immune system to detect and destroy cancer cells, and lead to new treatment options.

References:

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2. Ohta, Akio. “A metabolic immune checkpoint: adenosine in tumor microenvironment.” Frontiers in immunology. 7 (2016): 109.

3. Moreno Roig, Eloy, et al. “Prognostic role of hypoxia-inducible factor-2α tumor cell expression in cancer patients: a meta-analysis.” Frontiers in oncology. 8 (2018): 224.

4. Akinleye, Akintunde, and Zoaib Rasool. “Immune checkpoint inhibitors of PD-L1 as cancer therapeutics.” Journal of hematology & oncology. 12.1 (2019): 92.

5. Ge, Zhouhong, et al. “TIGIT, the next step towards successful combination immune checkpoint therapy in cancer.” Frontiers in Immunology. 12 (2021): 699895.

6. Zhao, J., et al. “The role of hypoxia-inducible factor-2 in digestive system cancers.” Cell death & disease. 6.1 (2015): e1600-e1600.

7. “About Lung Cancer.” American Cancer Society, January 2023. https://www.cancer.org/cancer/lung-cancer/about.html

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10. Sun, Yu, et al. “Combined evaluation of the expression status of CD155 and TIGIT plays an important role in the prognosis of LUAD (lung adenocarcinoma).” International immunopharmacology. 80 (2020): 106198.

11. Pawelczyk, Konrad, et al. “Role of PD-L1 expression in non-small cell lung cancer and their prognostic significance according to clinicopathological factors and diagnostic markers.” International journal of molecular sciences. 20.4 (2019): 824.

12. Banta, Karl L., et al. “Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses.” Immunity. 55.3 (2022): 512-526.

13. Guan, Shuxiao, et al. “Metabolic reprogramming by adenosine antagonism and implications in non-small cell lung cancer therapy.” Neoplasia. 32 (2022): 100824.

14. Sun, Changfa, Bochu Wang, and Shilei Hao. “Adenosine-A2A receptor pathway in cancer immunotherapy.” Frontiers in Immunology. (2022): 1195.

15. Chen, Siqi, et al. “The Expression of Adenosine A2B Receptor on Antigen-Presenting Cells Suppresses CD8+ T-cell Responses and Promotes Tumor GrowthAPC Expression of Adenosine A2BR Controls Tumor Growth.” Cancer immunology research. 8.8 (2020): 1064-1074.

16. Fares, Charlene M., et al. “Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients?” American Society of Clinical Oncology Educational Book. 39 (2019): 147-164.

17. Leone, Robert D., Ying-Chun Lo, and Jonathan D. Powell. “A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy.” Computational and structural biotechnology journal. 13 (2015): 265-272.

18. “How is Chemotherapy Used to Treat Cancer?” American Cancer Society, November 2019. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/how-is-chemotherapy-used-to-treat-cancer.html

19. “How Chemotherapy Drugs Work.” American Cancer Society, November 2019. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/how-chemotherapy-drugs-work.html

20. “About Colorectal Cancer.” American Cancer Society, June 2020 & January 2023. https://www.cancer.org/cancer/colon-rectal-cancer/about.html

21. “Treating Colorectal Cancer.” American Cancer Society, June 2020. https://www.cancer.org/cancer/colon-rectal-cancer/treating.html

22. Makaremi, Shima, et al. “Immune checkpoint inhibitors in colorectal cancer: challenges and future prospects.” Biomedicines. 9.9 (2021): 1075.

23. Hajizadeh, Farnaz, et al. “Adenosine and adenosine receptors in colorectal cancer.” International immunopharmacology. 87 (2020): 106853.

24. “About Prostate Cancer.” American Cancer Society, August 2019 & January 2023. https://www.cancer.org/cancer/prostate-cancer/about.html

25. “Treating Prostate Cancer.” American Cancer Society, August 2019. https://www.cancer.org/cancer/prostate-cancer/treating.html.

26. Venkatachalam, Shobi, et al. “Immune checkpoint inhibitors in prostate cancer.” Cancers. 13.9 (2021): 2187.

27. Fay, Andre P., and Emmanuel S. Antonarakis. “Blocking the PD-1/PD-L1 axis in advanced prostate cancer: are we moving in the right direction?.” Annals of translational medicine. 7.Suppl 1 (2019).

28. Mousavi, Samira, et al. “Expression of adenosine receptor subclasses in malignant and adjacent normal human prostate tissues.” The Prostate. 75.7 (2015): 735-747.

29. “Introduction to UGI Cancer.” National Cancer Institute. https://training.seer.cancer.gov/ugi/intro/.

30. “What is Stomach Cancer?” American Cancer Society. https://www.cancer.org/cancer/types/stomach-cancer/about/what-is-stomach-cancer.html.

31. “Adenocarcinoma.” National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/adenocarcinoma.

32. “Esophageal Cancer” National Cancer Institute: MyPART. https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-digestive-system-tumors/esophageal.

33. Then, Eric Omar, et al. “Esophageal Cancer: An Updated Surveillance Epidemiology and End Results Database Analysis. World Journal of Oncology. 11 (2020): 55-64.

34. “Review: Introduction to UGI Cancer.” National Cancer Institute. https://training.seer.cancer.gov/ugi/intro/review.html.

35. “Immunotherapy for Stomach Cancer.” American Cancer Society, February 2022. https://www.cancer.org/cancer/types/stomach-cancer/treating/immunotherapy.html.

36. “Immunotherapy for Esophageal Cancer.” American Cancer Society, June 2022. https://www.cancer.org/cancer/types/esophagus-cancer/treating/immunotherapy.html.

37. Cheng, Chao, et al. “Overcoming resistance to PD-1/PD-L1 inhibitors in esophageal cancer.” Frontiers in Oncology. 12 (2022): 955163.

38. Voutsadakis, Ioannis A. “A systematic review and meta-analysis of PD-1 and PD-L1 inhibitors monotherapy in metastatic gastric and gastroesophageal junction adenocarcinoma.” Euroasian journal of hepato-gastroenterology. 10.2 (2020): 56.

39. Wang, Daijun, et al. “Role of CD155/TIGIT in digestive cancers: promising cancer target for immunotherapy.” Frontiers in Oncology. 12 (2022).

40. “What is Pancreatic Cancer?” American Cancer Society, February 2019. https://www.cancer.org/cancer/types/pancreatic-cancer/about/what-is-pancreatic-cancer.html.

41. Sarantis, Panagiotis, et al. “Pancreatic ductal adenocarcinoma: Treatment hurdles, tumor microenvironment and immunotherapy.” World journal of gastrointestinal oncology. 12.2 (2020): 173.

42. “Survival Rates for Pancreatic Cancer.” American Cancer Society. March 2023. https://www.cancer.org/cancer/types/pancreatic-cancer/detection-diagnosis-staging/survival-rates.html.

43. Gallegos, Jillian M., et al. “Socioeconomic Factors Associated With a Late-Stage Pancreatic Cancer Diagnosis: An Analysis of the National Cancer Database.” Cureus 15.3 (2023).

44. Roth, Marc T., Dana B. Cardin, and Jordan D. Berlin. “Recent advances in the treatment of pancreatic cancer.” F1000Research. 9 (2020).

45. Brown, Timothy J., Kim A. Reiss, and Mark H. O’Hara. “Advancements in Systemic Therapy for Pancreatic Cancer.” American Society of Clinical Oncology Educational Book. 43 (2023): e397082.

46. Mohammed, Somala, I. I. George Van Buren, and William E. Fisher. “Pancreatic cancer: advances in treatment.” World journal of gastroenterology: WJG. 20.28 (2014): 9354.

47. “Immunotherapy for Pancreatic Cancer.” American Cancer Society, February 2019. https://www.cancer.org/cancer/types/pancreatic-cancer/treating/immunotherapy.html.

48. Liu, Lingyue, et al. “Combination therapy for pancreatic cancer: anti-PD-(L) 1-based strategy.” Journal of Experimental & Clinical Cancer Research. 41.1 (2022): 1-27.

49. Beatty, Gregory L., Shabnam Eghbali, and Rebecca Kim. “Deploying immunotherapy in pancreatic cancer: defining mechanisms of response and resistance.” American Society of Clinical Oncology Educational Book. 37 (2017): 267-278.

50. Coston, Tucker, et al. “Efficacy of Immune Checkpoint Inhibition and Cytotoxic Chemotherapy in Mismatch Repair-Deficient and Microsatellite Instability-High Pancreatic Cancer: Mayo Clinic Experience.” JCO Precision Oncology. 7 (2023): e2200706.

51. Faraoni, Erika Y., et al. “CD73-dependent adenosine signaling through Adora2b drives immunosuppression in ductal pancreatic cancer.” Cancer Research. 83.7 (2023): 1111-1127.

52. Graziano, Vincenzo, et al. “Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma.” Journal for Immunotherapy of Cancer. 11.8 (2023).

Investigating Combination Therapies to Treat Cancer

Current Status of Immunotherapy in NSCLC

Combination Strategies Under Investigation

Current Status of Immunotherapy in CRC

Combination Strategies Under Investigation

Current Status of Immunotherapy in Upper GI Cancer

Combination Strategies Under Investigation

Current Status of Immunotherapy in Pancreatic Cancer

Combination Strategies Under Investigation

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