IMMUNOTHERAPY IN CANCER

ASHA KARIPPOT MD

MEDICAL ONCOLOGIST

CANCER TREATMENT CENTERS OF AMERICA

Immunotherapy

• Chemotherapy- Is a type of cancer treatment which uses drug to kill cancer cells or stop them from dividing

• 2018-MD Anderson Immunologist Jim Allison was awarded Nobel prize in 2018 for his exciting work for launching an effective new way to attack cancer by treating the immune system rather than the tumor.

• Immunotherapy is increasingly identified as the best option for a growing number of cancers, many of which were previously intractable. The greatest success so far has been with immune checkpoint inhibitors and the U.S. Food and Drug Administration (FDA) has approved 15 indications for these agents over the last five years. Immunotherapy usage is likely to increase as we recognize encouraging results with several other specific classes of agents

• Immunotherapy is treatment that uses certain parts of a person’s immune system to fight diseases such as cancer. This can be done in a couple of ways:

• Stimulating, or boosting, the natural defenses of your immune system so it works harder or smarter to find and attack cancer cells

• Making substances in a lab that are just like immune system components and using them to help restore or improve how your immune system works to find and attack cancer cells

• As part of its normal function, the immune system detects and destroys abnormal cells and most likely prevents or curbs the growth of many cancers. For instance, immune cells are sometimes found in and around tumors. These cells, called tumor-infiltrating lymphocytes or TILs, are a sign that the immune system is responding to the tumor. People whose tumors contain TILs often do better than people whose tumors don’t contain them.

• Even though the immune system can prevent or slow cancer growth, cancer cells have ways to avoid destruction by the immune system. For example, cancer cells may:

• Have genetic changes that make them less visible to the immune system.

• Have proteins on their surface that turn off immune cells.

• Change the normal cells around the tumor so they interfere with how the immune system

responds to the cancer cells.

Types of Immunotherapy

• Immune check point inhibitors -drugs that block immune checkpoints. These checkpoints are a normal part of the immune system and keep immune responses from being too strong. By blocking them, these drugs allow immune cells to respond more strongly to cancer.

• Monoclonal antibodies, which are immune system proteins created in the lab that are designed to bind to specific targets on cancer cells. Some monoclonal antibodies mark cancer cells so that they will be better seen and destroyed by the immune system. Such monoclonal antibodies are a type of immunotherapy

• T-cell transfer therapy, which is a treatment that boosts the natural ability of your T cells to fight cancer. In this treatment, immune cells are taken from your tumor. Those that are most active against your cancer are selected or changed in the lab to better attack your cancer cells, grown in large batches, and put back into your body through a needle in a vein.

• Treatment vaccines, which work against cancer by boosting your immune system’s response to cancer cells. Treatment vaccines are different from the ones that help prevent disease.

• Immune system modulators, which enhance the body’s immune response against cancer. Some of these agents affect specific parts of the immune system, whereas others affect the immune system in a more general way

Immune check point inhibitors

• Checkpoint proteins, such as PD-L1 on tumor cells and PD-1 on T cells, help keep immune responses in check. The binding of PD-L1 to PD-1 keeps T cells from killing tumor cells in the body (left panel). Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (anti-PD-L1 or anti-PD-1) allows the T cells to kill tumor cells

FDA Approved Immunotherapies

• Ipilimumab(Yervoy)

• Pembrolizumab(Keytruda)

• Nivolumab(Opdivo)

• Atezolizumab (Tecenteriq)

• Avelumab (Bavencio)

• Durvalumab (Imfinzi)

• Cemiplimab (Libtayo)

• Melanoma

• Breast cancer

• Bladder cancer

• Cervical cancer

• Colon cancer

• Head and neck cancer

• Hodgkin lymphoma

• Liver cancer

• Lung cancer

• Renal cell cancer

• Skin cancer

• Stomach cancer

• Rectal cancer

• Any solid tumor that is not able to repair errors in its DNA that occur when the DNA is copied

• How do we/should we manage irAEs?

• What are the consequences of irAE management?

Why do irAEs happen?

What are common irAEs?

Incidence of irAEs Depends on the ICI

Why do irAEs happen?

APCs present tumor Ag to T cell via interaction of MHC and TCR- primary activating signal

Costimulatory signal is needed: B7 on APCs and CD28 on T cells

Coreceptors are negative modulators (CTLA-4 or PD-1). CTLA-4 is transported to surface in proportion to Ag stimulation- binds to B7 with greater affinity than CD28 causing inactivation.

PD-1 is a bit different- regulates inflammatory response in tissues by effector T cells. Activated T-cells upregulates PD-1 and inflammatory signals in the tissue induce expression of PD-L1, which decrease T cell activation and protect normal tissues

Precise mechanisms are unknown.

-Increasing T-cell activity against antigens that are present in the tumors and healthy tissue (box to L)- this may be particularly true for myocarditis- in two cases, T-cell infiltration of the myocardium was evident and similar T cell clones were found in both myocardium and tumor in one patient; vitiligo (autoimmune attack on melanocytes, most common in melanoma patients treated with ICI- cross reactivity between Ag on tumor and Ag in normal tissue)

-Autoantibodies (more than auto reactive T cells) may contribute differentially to some toxicities- thyroiditis- antithyroid antibodies can be detected- whether they were present at baseline or only after treatment initiation

-Cytokines: IL-17 seems to be involved in CTLA-4 colitis in patients and in pre-clinical models (raise the possibility of IL-17 blockade as a treatment ?)

-Increased complement mediated inflammation due to direct binding of anti-CTLA-4 Ab with CTLA-4 expressed on normal tissue- hypophysitis

How should we manage irAEs?

Pembrolizumab (200mg IV every 3 weeks)

3 months:

• Dyspnea on exertion

• 96% RA at rest

• 90% RA with ambulation

CT Angiogram

Negative for PE

IO Tox!

78 year old former smoker with oligometastatic adenocarcinoma of RUL, no targetable mutation, PD-L1 >50%

78 year old former smoker with oligometastatic adenocarcinoma of RUL, no targetable mutation, PD-L1 >50%

Radiographic presentations of ICI-related pulmonary toxicity are diverse and nonspecific

Pembrolizumab (200mg IV every 3 weeks)

3 months:

• Dyspnea on exertion

• 96% RA at rest

• 90% RA with ambulation

CT Angiogram

Negative for PE

IO Tox!

Treatment

Hold IO

Hospitalize?

1mg/kg oral prednisone

6 week taper

Prompt clinical improvement

Pembrolizumab (200mg IV every 3 weeks)

3 months:

• Dyspnea on exertion

• 96% RA at rest

• 90% RA with ambulation

CT Angiogram

Negative for PE

IO Tox!

Treatment

Hold IO

Hospitalize?

1mg/kg oral prednisone

6 week taper

Prompt clinical improvement

What if the patient doesn’t improve?

• 2 mg/kg

• Pulse steroids

• Infliximab

• Mycophenylate?

• Protect against opportunistic infections

Pembrolizumab (200mg IV every 3 weeks)

3 months:

• Dyspnea on exertion

• 96% RA at rest

• 90% RA with ambulation

CT Angiogram

Negative for PE

IO Tox!

Treatment

Hold IO

Hospitalize?

1mg/kg oral prednisone

6 week taper

Prompt clinical improvement

Majority of patients WILL NOT experience recurrent toxicity

Recurrent toxicity is likely to be steroid responsive and is NOTusually more severe than the initial toxicity

Risk:benefit Ratio

Restart IO?

αCTLA-4 + αPD-1

2 weeks:

•Abdominal pain

•Rectal bleeding

•Diarrhea (10 BM/day)

•3 point Hgb drop

•Creatinine doubled

Workup

Stool studies

•C. Diff

•Cultures

•Fecal leukocytes/lactoferrin

CT scan

•Wall thickening in distal colon

Colonoscopy

•Erythema and ulcers

Treatment

2 mg/kg IV steroid

Infliximab x2 doses

•5mg/kg → 10mg/kg

?Repeat endoscopy

•Infection? CMV?

Vedolizumab (Entyvio)

50 year old woman with Stage IV bladder cancer, POD after multiple lines of chemotherapy, enrolled in a trial of anti-CTLA-4 + anti-PD-1 antibodies

αCTLA-4 + αPD-1

2 weeks:

• Abdominal pain

• Rectal bleeding

• Diarrhea (10 BM/day)

• 3 point Hgb drop

• Creatinine doubled

Workup

Stool studies

• C. Diff

• Cultures

• Fecal leukocytes/lactoferrin

CT scan

• Wall thickening in distal colon

Colonoscopy

• Erythema and ulcers

Treatment

2 mg/kg IV steroid

Infliximab x2 doses

•5mg/kg → 10mg/kg

?Repeat endoscopy

•Infection? CMV?

Vedolizumab (Entyvio)

Vedo-WHAT?

• Monoclonal Ab used for IBD

• Target: Integrin α4β7

• 300 mg IV/dose

• Less systemic immunosuppression (gut specific)