Immunotherapy

Therapies that activate the patient’s immune system to destroy cancer are known as cancer immunotherapies. One type of immunotherapy consists of monoclonal antibodies. These are proteins that stick to one specific target typically expressed on cancer cells. Once bound to the cancer cell, monoclonal antibodies activate other parts of the immune system to destroy the cancer cell. 

Other types of cancer immunotherapies activate cells called T cells. T cells circulate throughout the entire body until they encounter a cancer cell. Once attached, T cells kill tumor cells and move on to recognize and kill other cancer cells. 

Cancer immunotherapies are arguably one of the most promising treatments for patients with advanced cancers such as melanoma and lung cancer. The results of various immunotherapy clinical trials have shown great promise, and immunotherapies are achieving responses never seen before in specific types of cancers. Below are examples of cancer immunotherapies and trials ongoing at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center.

Antibody-based Therapies

Checkpoint Inhibitors – Taking the Brakes Off the Body’s Immune System

Cancer cells put up defenses so they can’t be detected by the body’s immune system. One of the ways they do this is to render the immune system ineffective by presenting proteins that turn off response from T cells–the immune cells that kill tumor cells. Therapies known as “checkpoint inhibitors” work by blocking these proteins so that T cells can be activated to recognize cancer cells as foreign invaders.

One example of a checkpoint inhibitor is anti-CTLA-4. CTLA-4 is normally expressed on the surface of T cells. Tumor cells can activate the CTLA-4 pathway to suppress T cell activity. However, therapies such as ipilimumab block the CTLA-4 and restore tumor immunity.

Program death-1 (PD-1) is another protein found on the surface of T cells. PD-1 is a negative regulator of T cells and thus inhibits their antitumor responses. PD-1 interacts with PD-L1 and PD-L2 which are found on cancer cells as well as other types of cells within the tumor. Therefore, therapies that block PD-1 (such as pembrolizumab and nivolumab) or PD-L1 (atezolizumab) or PD-L2 can prevent the T cells from becoming suppressed and can reinvigorate antitumor immune responses.

Therapies that help maintain T cell function can also be used alone or in combination with checkpoint inhibitors to increase antitumor T cell responses. One such example is indoximod. Indoximod blocks the enzyme indoleamine 2,3-dioxygenase (IDO). Inhibiting IDO helps maintain high levels of an essential amino acid called tryptophan which is critical for T cell function. Another example is interleukin-2 (IL-2) therapy, a protein or cytokine that helps stimulate various types of immune cells including T cells. IL-2 has been approved for cancer treatment.   
 
Related Trials at UMGCCC

Disease Site(s)
Protocol Phase
Title   PI
Acute Myeloid Leukemia (AML)
1550GCC II Randomized Phase II Study to Assess the Role of Nivolumab as Single Agent to Eliminate Minimal Residual Disease and Maintain Remission in Acute Myelogenous Leukemia (AML) Patients After Chemotherapy Maria Baer, MD
Acute Myeloid Leukemia (AML) 1562GCC I/II A Phase 1b / Randomized Phase 2a Trial of Indoximod in Combination with Idarubicin and Cytarabine in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Ashkan Emadi, MD
Bladder  1680GCC  II  A Randomized, Double-Blind, Phase II Study of Maintenance Pembrolizumab versus Placebo after First-Line Chemotherapy in Patients with Metastatic Urothelial Cancer  Arif Hussain, MD 
Bladder, Lung, or Ovary  16101GCC  I A Phase 1 Study of the Safety and Pharmacokinetics of Escalating Doses of ASG-22CE Given as Monotherapy in Subjects with Metastatic Urothelial Cancer and Other Malignant Solid Tumors that Express Nectin-4  Heather Mannuel, MD
Lung (NSCLC)  1524GCC III A Phase III, Open Label, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) with a Platinum Agent (Cisplatin or Carboplatin) in Combination with Either Pemetrexed or Gemcitabine for PD-L1-Selected, Chemotherapy-Naïve Patients with Stage IV Non-Squamous or Squamous Non-Small Cell Lung Cancer Dan Zandberg, MD
Lung (NSCLC)  1607GCC I/II A Master Protocol of Phase 1/2 Studies of Nivolumab in Advanced NSCLC Using Nivolumab as Maintenance After Induction Chemotherapy or as First-Line Treatment Alone or in Combination with Standard of Care Therapies (CheckMate 370: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 370) Dan Zandberg, MD
Lung (NSCLC)  1629GCC II Randomized Phase II Trial Evaluating the Optimal Sequencing of PD-1 Inhibition with Pembrolizumab (MK-3475) and Standard Platinum-based Chemotherapy in Patients with Chemotherapy Naïve State IV Non-small Cell Lung Cancer
 
Dan Zandberg, MD
Lung (NSCLC) EA5142 III Adjuvant Nivolumab in Resected Lung Cancers (ANVIL) – A Randomized Phase II Study of Nivolumab After Surgical Resection and Adjuvant Chemotherapy in Non-small Cell Lung Cancers
 
Dan Zandberg, MD
Lung (NSCLC)  SWOG1400I  III A Phase III Randomized Study of Nivolumab Plus Ipilimumab Versus Nivolumab for Previously Treated Patients with Stage IV Squamous Cell Lung Cancer and No Matching Biomarker (Lung-MAP Sub-study)
 
Dan Zandberg, MD 
Pleural Mesothelioma  16100GCC  III  A Phase III, Randomized, Open Label Trial of Nivolumab in combination with Ipilimumab versus Pemetrexed with Cisplatin or Carboplatin as First Line Therapy in unresectable Pleural Mesothelioma  Dan Zandberg, MD
Various  1566GCC I A Phase 1, Open-Label, Dose Escalation Study of MGA271 in Combination with Pembrolizumab in Patients with B7-H3-Expressing Melanoma, Squamous Cell Cancer of the Head and Neck, or Non-Small Cell Lung Cancer, and Other B7-H3-Expressing Cancers  Dan Zandberg, MD

Monoclonal Antibodies (mAbs) – Synthetic Proteins Enhancing the Immune System

The immune system uses antibodies, or proteins, to recognize foreign invaders such as cancer cells. Monoclonal antibodies, or mAbs, are synthetic proteins that can bind to specific receptors (antigens) on cancer cells. Once bound to the antigen, mAbs signal to other parts of the immune system to come and destroy the cancer cell.

Related Trials at UMGCCC

Disease Site(s)  Protocol  Phase Title PI
Acute Lymphoblastic Leukemia (ALL) E1910 III A Phase III Randomized Trial of Blinatumomab for Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia in Adults
Maria Baer, MD
Acute Myeloid Leukemia (AML)  1564GCC  I Phase I Trial of Brentuximab Vedotin Combined with Re-induction Chemotherapy in Patients with Relapsed of Refractory, CD30-expressing Acute Myeloid Leukemia (AML)
Ashkan Emadi, MD
Bladder; Lung; Ovary  16101GCC I A Phase 1 Study of the Safety and Pharmacokinetics of Escalating Doses of ASG-22CE Given as Monotherapy in Subjects with Metastatic Urothelial Cancer and Other Malignant Solid Tumors that Express Nectin-4 Heather Mannuel, MD 
Breast  1594GCC II An Open-Label, Single-Arm, Phase II Study of Pertuzumab with High-Dose Trastuzumab for the Treatment of Central Nervous System Progression Post-Radiotherapy in Patients with HER2 Positive Metastatic Breast Cancer (PATRICIA)  Kate Tkaczuk, MD
Breast  1654GCC II  Phase II Randomized, Double-Blinded, Controlled Study of Tucatinib vs. Placebo in Combination with Capecitabine and Trastuzumab in Patients with Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma (HER2CLIMB) Kate Tkaczuk, MD 
Breast; Colon  1600GCC I GS-US-294-0101: A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GS-5745 as Monotherapy and in Combination with Chemotherapy in Subjects with Advanced Solid Tumors  Paula Rosenblatt, MD
Kidney 1638GCC II A Multi-Center, Open Label, Randomized Phase 2 Study of AGS-16C3F vs. Axitinib in Metastatic Renal Cell Carcinoma  Arif Hussain, MD
Multiple Myeloma  16102GCC  II Phase II, Randomized, Open-Label Study Comparing Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) Versus Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) in Patients With Newly Diagnosed Multiple Myeloma Eligible for High-Dose Chemotherapy and Autologous Stem Cell Transplantation Ashraf Badros, MD
Ovary 1533GCC II A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Efficacy and Safety of Farletuzumab (MORAb-003) in Combination with Carboplatin plus Paclitaxel or Carboplatin plus Pegylated Liposomal Doxorubicin (PLD) in Subjects with Low CA125 Platinum-Sensitive Ovarian Cancer
Gautam Rao, MD
Pediatric B-Lymphoblastic Leukemia  AAL1331  III Risk-Stratified Randomized Phase III Testing of Blinatumomab (IND# 117467, NSC#765986) in First Relapse of Childhood B-Lymphoblastic Leukemia (ALL)
Teresa York, MD
Pediatric Hodgkin's Lymphoma AHOD1331  III A Randomized Phase III Study of Brentuximab Vedotin (Bv, IND #117117) for Newly Diagnosed High-Risk Classical Hodgkin Lymphoma (CHL) in Children and Adolescents
Teresa York, MD
Pediatric
Soft Tissue 
AEWS1221  II Randomized Phase II Trial Evaluating the Addition of the IGF-1R Monoclonal Antibody Ganitumab (AMG 479, NSC# 750008, IND# 120449) to Multiagent Chemotherapy for Patients with Newly Diagnosed Metastatic Ewing Sarcoma Teresa York, MD 

 

Cancer Vaccines – Training the Immune System to Recognize Cancer

Related Trials at UMGCCC

Disease Site(s)  Protocol Phase Title PI
Breast 1604GCC II A Randomized Multicenter Phase II Trial to Evaluate the Safety and Immunogenicity of Two Doses of Vaccination with Folate Receptor Alpha Peptides with GM-CSF in Patients with Triple Negative Breast Cancer
Kate Tkaczuk, MD
Head and Neck  1666GCC II  A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Determine the Safety and Efficacy of GL-0817 (with Cyclophosphamide) for the Prevention of Recurrence in HLA-A2+ Patients with High-Risk Squamous Cell Carcinoma of the Oral Cavity  Dan Zandberg, MD 
Multiple Myeloma 1611GCC II Phase II Multicenter Trial of Single Autologous Hematopoietic Cell Transplant Followed by Lenalidomide Maintenance for Multiple Myeloma with or without Vaccination with Dendritic Cell/Myeloma Fusion  Aaron Rapoport, MD
Prostate  1404GCC III A Randomized, Double Blind, Multicenter, Parallel-Group, Phase III Study to Evaluate Efficacy and Safety of DCVAC/PCa Versus Placebo in Men with Metastatic Castration Resistant Prostate Cancer Eligible for 1st Line Chemotherapy  Arif Hussain, MD

1562GCC

 

Gene-modified Immune Cells

Thanks to advances in modern genetics, it is now possible to extract a patient’s own T cells, genetically modify them in ways that make them more effective in detecting and fighting cancer, and deliver them back to the patient. This approach was first pioneered at UMGCCC for the treatment of blood cancers, and now researchers are using gene-modified T cells to equip patients’ immune systems to fight non-small cell lung cancer. 

Related Trials at UMGCCC

Disease Site(s)  Protocol  Phase Title PI
Acute Lymphoblastic Leukemia  1567GCC I/II  Phase 1/2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 in Adult Subjects with Philadelphia Chromosome-Negative Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia  Maria Baer, MD 
Lung and Other Respiratory and Intrathoracic Sites 1555GCC  I/II A Phase I/II Open Label Clinical Trial Evaluating the Safety and Efficacy of Autologous T Cells Expressing Enhanced TCRs Specific for NY-ESO-1 in Subjects with Stage IIIb or Stage IV Non-Small Cell Lung Cancer (NSCLC) Nancy Hardy, MD
Lung and Other Respiratory and Intrathoracic Sites 1556GCC  I/II A Phase I/II Dose Escalation Open-Label Clinical Trial Evaluating the Safety and Efficacy of MAGE-A10c796T in Subjects with Stage IIIb or Stage IV Non-Small Cell Lung Cancer (NSCLC) Nancy Hardy, MD

 

Combination Therapies

Sometimes immunotherapies are rendered more efficacious when combined with other modalities. For example, radiation therapy and immunotherapy used together can create a synergistic result greater than the sum of its parts.

Related Trials at UMGCCC

Disease Site(s)  Protocol Phase Title PI
Brain  1344GCC  Pilot Pilot Study of Combined Optune, Bevacizumab, and Hypofractionated Stereotactic Irradiation for Bevacizumab-Naïve, Recurrent Glioblastoma  Young Kwok, MD
Head and Neck  1456GCC II A Phase II Trial of Reirradiation Combined with Open Label MK-3475 in Patients with Locoregional Inoperable Recurrence of Second Primary Squamous Cell Carcinoma of the Head and Neck (SCCHN)  Dan Zandberg, MD
Head and Neck  0920RTOG  III A Phase III Study of Postoperative Radiation Therapy (IMRT) +/- Cetuximab for Locally-Advanced Resected Head and Neck Cancer  Mohan Suntha, MD
Soft Tissue (Sarcoma)  1711GCCC I/II Neoadjuvant Anti-PD-L1 (Durvalumab/MEDI4736) Plus Anti-CTLA-4 (Tremelimumab) and Radiation for High Risk Soft-Tissue Sarcoma Vincent Ng, MD