The SU2C-CRI Immunology Dream Team Progress Update
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The SU2C-CRI Immunology Dream Team Progress Report
Immunologic Checkpoint Blockade and Adoptive Cell Transfer in Cancer Therapy
Funding: $10 million + $1 million MRA supplement
Leader: James P. Allison, Ph.D., The University of Texas MD Anderson Cancer Center
Antoni Ribas, M.D., Ph.D., University of California, Los Angeles
Co-Leader: Drew M. Pardoll, M.D., Ph.D., Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center
Cassian Yee, M.D., The University of Texas MD Anderson Cancer Center
Fast Facts on Immunotherapy:
- Cancer immunotherapy harnesses the body’s own immune system to attack cancers, and is a promising and rapidly growing area in cancer research and treatment.
- Ipilimumab, pembrolizumab, and nivolumab, drugs that reverse the tumor’s ability to suppress anti-cancer immunity, are the first immune therapies to receive FDA approval. They are approved for treatment of metastatic melanoma and some lung cancers and are being tested in many other cancers.
The Immunology Dream Team’s Research Project
Cancer immunotherapy is based on getting a patient’s own immune system to attack their cancer. This Dream Team is working on two uniquely successful and complementary approaches to cancer immunotherapy. In one approach, drugs called checkpoint inhibitors are used to foil the “tricks” that cancers rely on to escape natural immune cell attack. In the other approach, known as adoptive cell transfer (ACT), patients’ own immune cells are taken to the lab, made into efficient cancer killing “armies” and returned to the patient. By optimizing these two approaches, as well as combining them, this Dream Team expects to achieve long-lasting responses in a large percentage of patients suffering from a variety of types of cancer.
The body’s major cancer cell killing immune cell is a type of white blood cell called a T-lymphocyte, or T cell. T-lymphocytes use a molecule called a T cell receptor (TCR) to recognize “flags”, called antigens, on cancer cells and then kill the cancer cell. Cancer, however, can escape these immune attacks using molecules called checkpoints, which work like the brakes on a car stopping the T-lymphocytes from doing their cancer-killing jobs. To overcome these obstacles this Dream Team is using drugs called checkpoint blockers to “disable the brakes.” Work by members of this Dream Team, has contributed to FDA approval of two new checkpoint inhibitors, pembrolizumab and nivolumab, in 2014. The Dream Team is analyzing tumor samples to determine how checkpoint inhibitors work and to identify biomarkers, molecules that can be measured in patients’ blood, tumor samples, or other biological specimens, that can predict which patients will respond to immune therapy.
The team is also pursuing multiple ways to make better T-lymphocytes for ACT. They are testing which antigen “flags” are expressed by tumor cells to find out how best to target the T-lymphocyte attack, and whether they can personalize immune-therapy to the “flags” present on individual patients’ tumors. In some studies they are isolating small numbers of T lymphocytes with the desired ability to recognize and kill cancer, expanding their numbers in the laboratory, and then giving them back to the patient. Alternatively, they are using gene transfer techniques to take the antigen-recognizing TCR from one T lymphocyte that is cancer specific and insert it into many other T lymphocytes so that they then become cancer-specific. The Dream Team is also using artificial receptors based on antibodies, termed chimeric antigen receptors (CAR), to redirect the killing ability of T cells and restrict it to cancer cells.
Building on their expertise in these cutting edge approaches to immune therapy, this Dream Team is performing some of the first clinical studies combining checkpoint inhibition with ACT, to maximize the benefit to patients.Status Update:
In the first six months, the Dream Team has reported a significant amount of progress towards their aims.
Substantial progress has been made in characterizing the tumor microenvironment before and after checkpoint blockade. In addition, the investigators from The University of Texas MD Anderson Cancer Center have received institutional review board (IRB) approval for an institution-wide biospecimen collection protocol from all immune therapy protocols conducted at the institution. This language has been provided to the other institutions in the Dream Team with the intent that a harmonized protocol can enable specimen analysis for all patients on all trials conducted by the Dream Team.
Another core piece of infrastructure that has begun implementation is a bioinformatics system (Prometheus) that can merge clinical data and laboratory data from the analysis of specimens that are collected across the different sites. The Dream Team has also begun implementation of a platform for staining and analyzing tumor biopsies for checkpoint molecule expression.
The projects related to optimizing ACT approaches are just beginning; however, the Dream Team noted that one trial is already open with two of the targeted 22 patients already enrolled. Three additional clinical trials investigating ACT are currently awaiting Institutional Review Board approval.
In the second 6 months of support, this Dream Team continues to make significant progress. An initial clinical trial of 10 patients with metastatic melanoma who underwent adoptive cell transfer (ACT) combined with checkpoint blockade (anti-CTLA-4; ipilimumab) showed either regression or no further progression in 7 of the 10 patients. These promising studies will be followed up in an extended study that adds 20 more patients. If successful, these studies may establish a regimen that is relatively safe and provides significant anti-tumor efficacy in this disease.
Other clinical trials by members of this Dream Team focused on ACT and on the combination of ACT with checkpoint blockades or blockers of tumor blood vessel growth continue to move through the important clinical trial approval process before patient enrollment can begin. One ACT trial at ULCA is enrolling patients while another trial, which combines two different checkpoint blockade drugs in patients with advanced or metastatic solid tumors, is now ready to open.
This Dream Team has also had success in their efforts to identify the best antigen targets on cancer cells for ACT. Dream Team members have identified a molecule called mesothelin as a potential biomarker and a candidate for targeted ACT in lung cancer. Preparation for an ACT clinical trial of mesothelin targeted T cells in lung cancer is moving forward.
Across these clinical trials and other studies, analysis of tumor tissues and blood will allow a broad analysis of biomarkers. Results from the analyses will help in selecting appropriate patients to maximize the benefit and minimize severe toxic side-effects, as well as identify cancer cell antigens and new immune checkpoint molecules from which novel therapeutic targets may arise.
This Dream Team has continued to make progress during the 13-18 month period of support:
- A number of planned trials of checkpoint therapy are either open or in the final stages of approval.
- New promising trials of adoptive cell therapy (ACT), alone or in combination with checkpoint inhibitors, are also now open or close to approval.
- Genetic changes and biomarkers that can predict which patients will respond to specific immune therapies are being identified.
- They are developing algorithms to identify and predict the best “flags”, called antigens, on cancer cells that can be used to target T-cell therapies in a range of cancers.
- They are trying to identify the best approaches to increase the strength of immune cells for adoptive cell therapy.
Significant progress has been made by this Dream Team in their 18-24 month funding. They report:
- Opening of six new immune therapy clinical trials, two of which combine treatment of cancer- targeted T cells with checkpoint inhibitor drugs that reverse suppression of immune cells in tumors.
- Development of new approaches to predict who will benefit from checkpoint inhibitor drugs.
- Identification of “flags” that appear specifically on cancer cells and can signal to immune cells activating them to attack the cancer. By understanding these “flags”, the Dream Team hopes to specifically activate anti-cancer immune cells and to personalize immune therapeutic approaches to individual patient’s tumors.
In the 25-30 month funding period the Dream Team reports continued progress:
- Continued enrollment of patients to clinical trials in at least a dozen different cancer types.
- Opening of three new immune therapy clinical trials. Two of these are new adoptive cell therapy (ACT) trials in lung cancer.
- New information on why some people respond very well to checkpoint inhibitors while others do not respond and/or develop resistance over time.
- Progress on discovering new “flags” on cancer cells that can be used to drive immune cells to attack and kill cancer cells efficiently and specifically.
In the 30-36 month funding period the Dream Team reports progress as follows:
- They have continued to enroll patients in their clinical trials across a range of human cancers and are close to opening two new trials in ovarian cancer.
- They have continued their work cataloging new antigen “flags” that can signal to anti-cancer T cells in melanoma.
- They have identified a new antigen “flag” on melanoma cancer cells, as well as pancreatic cancer cells, which may be used to develop new immunotherapies.
- They have gathered new information on how some patients are resistant, or become resistant, to checkpoint blockers like nivolumab (Opdivo) and pembrolizumab (Keytruda).
- They have made progress in improving the quality and activity of genetically engineered anti-tumor T cells and are adapting this therapy for patients with common solid tumors such as lung cancer.
- The have developed a very sensitive way to look at T cells from patients and find out which antigen “flags” the T cells can recognize on tumor cells. This work may help the Dream Team move closer to personalized immunotherapy based on each patient’s own tumor antigens.
In the 36-42 month funding period the Dream Team reports continued progress on all specific aims as follows:
- They have identified new checkpoint molecules in prostate tumors that may allow these tumors to circumvent current checkpoint blockade treatments, which are targeted at CTLA4 and PD-1. These data may allow development of new checkpoint blockage drugs that can be used to enhance the effects of CTLA1 and PD-1 clockers.
- They have developed two new “flags” on cancer cells – one in uveal melanoma and the other in a range of non-melanoma solid tumors – for adoptive cell therapies to test in combination with checkpoint blockade in first-in-human clinical trials.
- They have determined that there are larger than expected numbers of anti-cancer immune T cells that appear to be naturally active against cancer-specific “flags”, called neoantigens, in tumors where the number of neoantigens is generally low. These data are encouraging that difficult-to-treat cancers may be responsive neoantigen-targeted immunotherapies.
- The Dream Team’s Phase 2 clinical trial of the PD-1 blocker nivolumab (Opdivo) as a pre-surgical treatment in early stage non-small cell lung cancer has produced positive results with >90% reduction in tumor size in almost half of patients tested (six of 13 patients). Based on these promising results a Phase 3 trial is planned.