Local and intra-tumoural immunotherapy

Question 1

Immunotherapy can be incredibly effective on cancer, but sometimes can have horrible side effects. What are possible solutions to the side effects?

Answer 1

Local application of low-dose immune checkpoint inhibitors rather than high-dose systemic

Question 2

What are 3 hurdles of immunotherapy of cancer and what is a solution?

Answer 2

1. Tumour heterogeneity and neoantigen polyclonality that hamper T cell immunity
2. Neo-epitopes are mostly non-driver mutations: risk of loss and immune escape
3. Co-evolution of tumour, neoantigen repertoire and microenvironment leads to profound and diverse immune suppression

Solution: early, local intervention

Question 3

What are 8 things to consider when designing an intra-tumoural immunotherapy trial?

Answer 3

Dose determination
Efficacy
Dose escalation
Intratumoral injection
Patient exclusion criteria
Trial design
Pharmacokinetics
Pharmacodynamics

Question 4

What are three instances of local cancer immunotherapy?

Answer 4

1. Oncolytic viruses
2. Local tumour ablation
3. Immune modulation of tumour draining lymph nodes

Question 5

How do oncolytic viruses work?

Answer 5

They only target (infect) cancer cells. This leads to local inflammation, release of virus progeny (which will infect more cancer cells) and release of tumour antigens (which induces a systemic anti-tumour response).

Question 6

What are 3 novel insights about tumour draining lymph nodes and DCs?

Answer 6

3 novel insights about tumour draining lymph nodes and DCs:

1) Tumour Draining Lymph Nodes (TDLN) are vital for effective PD-(L)1 or CTLA-4 blockade
2) Tumour Infiltrating DCs are also vital for Tumour Infiltrating Lymphocyte recruitment, activation and survival
3) Effective PD-L1 blockade involves DC-mediated T cell expansion in TDLN rather than “just” reversal of an “exhausted” T cell state (in the TME)

Question 7

Where does the efficacy of melanoma immunotherapy depend on?

Answer 7

Dendritic cells.

Tumour Draining Lymph Node (TDLN) mass cytometry can be used to safeguard proper DC differentiation in melanoma.

Question 8

What role does the Wnt pathway play in melanoma?

Answer 8

The Wnt pathway causes T-cell and DC infiltration and an inflamed tumour type.

Question 9

What kind of virotherapy might help effective immune checkpoint blockade?

Answer 9

Ad-CA.GSK3β virotherapy might help effective immune checkpoint blockade

Question 10

How do you clinicaly arm the sentinal lymph node?

Answer 10

Clinical arming of the Sentinel Lymph Node (N.B.: solely effects TDLN after tumour removal):

1. i.d. (intradermal) injections of saline/CpG-B at tumour excision site in week prior to SNB
2. Surgical removal of SLN
3. Scraping of the SLN cutting surface: isolation of viable cells
   a. Transcriptional profiling
   b. Phenotypic characterization
   c. Flowcytometry or mass cytometry

Question 11

Is irreversible electroporation viable as in vivo vaccination?

Answer 11

Irreversible electroporation causes a shift in Treg-Teff cells and a boosted WT-1 T cell response in PDAC (pancreatic ductal adenocarcinoma). A WT-1 T cell response is related to overall survival.