Systemic immunotherapy for solid tumours

Question 1

How did the idea for (systemic) immunotherapy for cancer start?

Answer 1

In 1866 (Busch) & 1891 (Coley), doctors discovered bacterial infection on tumour site could increase patient outcome. In the 2010s, an increasing number of immune related therapies for cancer start coming on the market.

Question 2

How long is the response for immunotherapy?

Answer 2

Immunotherapy has more durable responses (=% alive after 2 years stays stable and higher than chemotherapy and targeted therapy).

Question 3

What is further research in cancer immunotherapy focused on?

Answer 3

Further research in cancer immunotherapy is focused on:
o Biomarkers for patients selection and response to treatment
o Mechanisms of primary and secondary resistance
o Best timing of immunotherapy
o Best combination with other treatment entities

Question 4

What are the response rates of immune checkpoint inhibitors in most cancers?

Answer 4

In most cancer response rates are 20-30%

Question 5

In which cancers does anti-PD-(L)1 work?

Answer 5

It works in a lot of solid tumours, but not in prostate cancer, myeloma, MMR+ (MSS) colon cancer and pancreatic cancer. The first succes was in melanoma, where it worked better than chemotherapy (70% vs 20% 18 month survival). The biggest response rate is in Hodgekin lymphoma

Question 6

What are the differences between immunotherapy and chemotherapy?

Answer 6

Well tolerated: some nausea, no hair loss, no neutropenia.
Good safety profile
Most serious adverse events are inflammation-mediated, like pneumonitis, myocarditis, colitis, hypophysitis.

Question 7

What is difficult about immunotherapy in cancer for the physicians?

Answer 7

Physicians will have to learn to manage a different spectrum of adverse events than those seen in chemotherapy. There can also be pseudoprogression, where the tumour progresses under immunotherapy treatment, before regressing.
When pseudoprogression happens, the therapy still works, but it is scary

Question 8

What are the immune Related Adverse Events in clinical trials with anti-CTLA4, anti-PD-1 or anti-PD-L1 antibodies as single therapy like? Compare them with each other.

Answer 8

Immune Related Adverse Events in clinical trials with anti-CTLA4, anti-PD-1 or anti-PD-L1 antibodies as single therapy:
•CTLA-4 most adverse events (both low and high grade)
•PD-1 a lot of low grade adverse events, but very little high grade
•PD-L1 very little adverse events (both low and high grade)

Question 9

How do we predict the response to ICI?

Answer 9

PD-L1 expression is not a good biomarker. The composition of the TME matters: immune desert, immune excluded or inflamed. Tumour inflammation signature has a significantly better predictive value than PD-L1 expression

Question 10

In which types of gastric cancer is immunotherapy the most succesful?

Answer 10

Immunotherapy most successful in EBV and MSI cases

Question 11

What are questions to consider to improve responses for non-T-cell inflamed cancers?

Answer 11

•Are we targeting the wrong immune cells?
•Do we have to target pathways of immune suppression?
•How do we make cold/excluded tumours hot?
o Increase immune cell recognition:
Combination treatment with:
•Vaccine or oncolytic virus (like T-VEC)
•Adoptive T-cell transfer/CAR-T-cell therapy
•Radiotherapy
o Increase cell infiltration/effector function:
Combination treatment with:
•Angiogenesis inhibition
•Targeted therapies